Patients treated with **ketamine** experience an exacerbation of positive and negative system, suggesting that NMDAR antagonists affect a brain system that is already vulnerable in schizophrenia (Javitt, 2010). Similar to healthy humans, animals treated with ketamine exhibit behavioral and electrophysiological features that closely resemble schizophrenia. Consistent with results in human, studies have demonstrated that acute ketamine administration decreases the amplitude and latency of the mouse N40 and P80 mimicking schizophrenia-like abnormalities on those components (Connolly et al., 2004, Maxwell et al., 2006a). However, a study by de Bruin and colleagues (de Bruin et al., 1999) reported that acute ketamine had no effect on gating of the N40 and P80 components. However, De Bruin confirmed that ketamine selectively decreased the amplitude of P80 in awake rats (de Bruin et al., 1999). Furthermore, mice undergoing 14 days of chronic ketamine (daily acute administration) showed lasting effects of long-term ketamine exposure such as decreased N40 amplitude (Maxwell et al., 2006a). Reduced ability to detect changes in the auditory environment is a further characteristic of schizophrenia which can be addressed by administering ketamine to rodents. Ketamine has been reported to impair gating of responses to repeated clicks presented at 100ms intervals (Boeijinga et al., 2007). While some studies have reported ketamine to disrupt MMN (Connolly et al., 2004, Bickel and Javitt, 2009, Ehrlichman et al., 2009a), others observed no significant effects (de Bruin et al., 1999, Connolly et al., 2004, Heekeren et al., 2008). In animals, ketamine disrupted the auditory gating and MMN with deficits similar to those seen in schizophrenia (Miller et al., 1992, Tikhonravov et al., 2008). Thus, deviance-elicited changes in N40 amplitude and in the subsequent temporal region between 50-75 msec (late N40 negativity) are observable, which displays characteristics similar to those seen with MMN in humans. Ehrlichman and others have found that ketamine attenuates both of these responses (Ehrlichman et al., 2008). These findings are important for several reasons. (1) They bolster the link between deviance detection and the NMDA receptor system. (2) They support the hypothesis that mouse N40 is the analogous to the human N100 which finally (3) demonstrates the feasibility of ketamine as a NMDAR antagonist to be a model of schizophrenia. Using the auditory click paradigm, Lazarewicz and others investigated the effect of ketamine on background, evoked, and induced power (Lazarewicz et al.). While low dose of ketamine (5mg/kg) only affected background power in the theta range, the higher dose (20mg/kg) significantly increased background power in theta and gamma range. Additionally, they observed a decrease in evoke theta power (3-12Hz) and an increase in evoked gamma power. Similar findings were replicated in rats as well as in humans (Hahn et al., 2006, Hong et al.). The reports of gamma power abnormalities highly diverge. Reduction on gamma power and synchronization are frequently reported in schizophrenia (Haig et al., 2000, Gallinat et al., 2004, Uhlhaas and Singer). However, inconsistent data exist (Lee et al., 2003, Spencer et al., 2003). Acute brain slice preparations have also been used to investigate gamma synchrony in pharmacologic models of schizophrenia. Such paradigms have demonstrated strikingly divergent results from the in vivo studies described above. Whereas in vivo studies

schizophrenia.

demonstrated consistent brain-region independent increases in gamma activity with ketamine, slice studies reported increased gamma power only in auditory cortex with no changes in other cortical regions.

**Phencyclidine (PCP)** and other dissociative PCP-like drugs (e.g., MK801) are extensively applied to model schizophrenia, in particular due to its ability to mirror the symptomatology of schizophrenia including positive, negative, and cognitive symptoms (Bodi et al., 1959, Javitt et al., 1987). Especially, psychosis induced by PCP gained great interest since it reflects fairly well clinical features of the schizophrenia psychosis. Rats exposed to acute PCP display an impaired sensory gating, in particular of N2. Furthermore, Dissanayake and others found PCP to disrupt the gating of N2 in cortical and hippocampal areas (Miller et al., 1992, Mears et al., 2006, Dissanayake et al., 2009). Clozapine, an atypical neuroleptic, prevented the disruption in gating which stands in agreement with human studies demonstrating successful reversal of sensory gating deficits in schizophrenia (Nagamoto et al., 1996, Adler et al., 2004). Furthermore, schizophrenia-like abnormalities in MMN generation have been demonstrated by exposing monkeys to PCP (Javitt et al., 2000). Notably, PCP inhibited the N1 and P1 generation at long inter-stimulus-intervals (ISI), while at short ISI their generation was unaffected. Further, phencyclidine increases gamma frequency power, in particular in the hippocampus (Ma and Leung, 2000). Furthermore, an elevation in hippocampal theta power is observable following PCP administration. In contrary, total cortical power was reported to be decreased. Perinatal PCP exposure was found to result in long-lasting deficits in sensory gating, cognitive, and executive functioning in adult mice. Furthemore, atypical antispsychotics reverse these impairments. These biochemical and behavioral changes phenotipically resemble observations seen in schizophrenia and may serve as a model of the development of schizophrenia (Broberg et al., 2008, Wang et al., 2008).

Finally, **Dizocilpine (MK801)** is frequently used as an animal model of schizophrenia (Fletcher et al., 1989). However, in human research ketamine/PCP are used instead of MK801 due to its severe neurotoxicity. A single injection of MK801 is sufficient to model positive and negative symptoms. Animals treated acutely with MK801 mimic successfully the features of psychosis. Higher doses of MK-801 produce changes in brain activity accompanied by strong behavioral effects involving impaired locomotor control (Kovacic and Somanathan). Specifically, MK801 significantly augments low frequencies (1-6Hz) in cortical and amygdalar areas, while it concomitantly reduces higher frequencies (16-32Hz) (Ehlers et al., 1992). Also, the deficit in P200 gating seen in schizophrenia can be mimicked in the mouse correlate P80 by administrating MK801 (Ehlers et al., 1992). Finally, MK801 was shown to dose-dependently block the generation of MMN in unanesthetized monkeys and anesthetized rats (Javitt et al., 1996, Tikhonravov et al., 2008).

In summary, pharmacological approaches targeting NMDAR are effective tools in examining the pathophysiology of schizophrenia. Compared to other pharmacological animal models of schizophrenia, the NMDAR antagonist model provides clinical parallels allowing researchers to translate findings and treatment strategies from animal into human studies. A further advantage is the fact that acute exposures of above reviewed NMDAR antagonist induce schizophrenia-like symptomatology in healthy individuals lasting several hours up to days (Bakker and Amini, 1961). However, NMDAR antagonists produce acute receptor hypofunction and therefore fail to reflect chronic, developmental disruption in glutamatergic signaling that may underlie schizophrenia pathogenesis. Collectively, these virtues exemplify reasons for NMDA model in providing useful strategies to identify neural

Electrophysiological Deficits in Schizophrenia: Models and Mechanisms 41

disturbances that cause the phenotype of schizophrenia, and nicotine is shown to affect this

Since MMN deficits are thought to indicate degraded auditory perception experienced by schizophrenia patients, it follows that the effect of nicotine administration on schizophrenia symptoms be assessed using this measure. In the schizophrenia-free population, nicotine has been shown to enhance MMN amplitudes and shorten MMN latencies (Inami et al., 2005, Martin et al., 2009). Further evidence for the role of nicotine in ameliorating the MMN deficit emerges from the administration of the nicotinic agonist AZD3480, selective for the alpha-4-beta-2 subtype. As such, AZD3480 significantly increases the MMN amplitude and reduces the MMN latency, at the same time significantly enhancing scores in cognitive tests of attention and episodic memory when administered chronically for ten days (Dunbar et al., 2007). Human studies directly assessing the effects of nicotine on individuals with schizophrenia are few in number and exhibit mixed results. Acute nicotine transiently normalized the amplitude of MMN in response to duration but not frequency changes in auditory stimuli (Dulude et al., 2010). Inami found that acute transdermal nicotine in nonsmokers reduces the MMN latency in healthy subjects, but not in patients with schizophrenia (Inami et al., 2007). This finding could be unique to the schizophrenia population that refrains from smoking and may reflect either differential drives to smoke based on symptom alleviation or be affected by the myriad of neuronal adaptations that chronic nicotine exposure induces, creating two distinct populations in schizophrenia. More studies are needed to elucidate the role of nicotinic receptors on MMN performance. There are several issues that limit nicotine being used as therapeutic drug. The ubiquity of nicotine receptors in the CNS and PNS make it difficult for a drug to target a specific region of the brain. A therapeutic drug's binding specificity and route of administration would therefore have to be optimized so as to minimize drug side affects. Nicotine itself has a short half-life. The rapid metabolism of the drug and its transient effects would mean that a mechanism of sustained release would need to be employed for the agent to remain active for an extended period of time. However, a direct impediment to this therapeutic modification is that nicotinic receptors exhibit quick desensitization. This would mean target receptors might not be available for binding and drug efficacy. These factors must be addressed before nicotine can be seriously considered as a candidate as a therapeutic drug for schizophrenia patients. There are currently several drugs that act at the nAChR that show promise. Agonists like DMXBA have been shown to successfully overcome several of these pharmacological challenges and stand as contenders for therapeutic relief (Martin and Freedman, 2007). Other options include the use of a positive allosteric modulator to enhance

the efficacy of the receptor without directly activating it (Gronlien et al., 2007).

Schizophrenia carries an important genetic contribution with a heritability of approximately 80% (Sullivan et al., 2003). ERPs deficits, particularly of the P50, N100, P300 and MMN components are among the most heritable (approximately 70%) and reproducible phenotypes of schizophrenia (Frangou et al., 1997, Ahveninen et al., 2006, Hall et al., 2006, Turetsky et al., 2007a). Whereas the number of candidate genes for schizophrenia is estimated to be over 1000, a subset of specific genetic contributions have been directly associated with ERPs. These genes are mostly involved in dopaminergic, nicotinic and glutamatergic mechanisms. For example, P50 gating deficits have been linked to the alpha-7

**4.2.2 Transgenic approaches**

mechanism.

endophenotypes in regard to development of new therapies to target treatment-resistant symptoms.

**Nicotine**. Nicotine has generated interest as a candidate for therapeutic use in alleviating schizophrenia symptoms. Individuals with schizophrenia are three times more likely to smoke and have high nicotine dependence compared to the general population (Hughes et al., 1986, de Leon and Diaz, 2005). They also have lower smoking cessation rates and selfadminister more nicotine during cigarette smoking than control patients, a finding supported by measuring cotinine, a nicotine metabolite used as a biomarker of tobacco exposure (Olincy et al., 1997, de Leon and Diaz, 2005). This, along with the known prevalence of genotype differences leading to the loss of function in the alpha 7 nicotinic receptor found in individuals with schizophrenia, (Adler et al., 1998, Leonard et al., 2001, Picciotto and Zoli, 2008) supports the idea that individuals with schizophrenia selfadminister nicotine as a form of self-medication to rectify deficits in neurocognitive performance and alleviate symptoms associated with the disease (Dalack and Meador-Woodruff, 1996, Kumari and Postma, 2005, Kumari et al., 2006)(Dalack and Meador-Woodruff, 1996).As mentioned previously, individuals with schizophrenia exhibit a higher ratio between the second and first stimulus in the auditory gating paradigm reflecting a dysfunction in stimulus processing. Acute nicotine in humans transiently normalizes the P50 gating deficit. This is observed with cigarette smoking in schizophrenia patients (Adler et al., 1993)as well as in studies using nicotine-containing gum in non-smoking family members of schizophrenia patients who exhibited P50 gating deficits (Adler et al., 1992). Mice undergoing 14 days of chronic nicotine increased both in the amplitude and gating of the P20, while having only acute nicotine decrease the amplitude and gating of N40(Metzger et al., 2007). A variety of pharmacological models further demonstrate the importance of the nAChr in stimulus gating. nAChR agonists display similar affects to nicotine. Acute administration of DMXB-A, a nicotinic agonist specifically targeting the alpha7 nicotinic, significantly suppressed the P50 of the test stimulus in subjects with schizophrenia, bringing the gating of the schizophrenia patients into the range of controls (Meyer et al., 1997, Olincy et al., 2006). These results were consistent with animal model studies testing the same drug(Stevens et al., 1998). Administration of 5-I A-85380, an alpha4beta2 nAChR agonist, in DBA/2 mice also significantly reduced the second to first stimulus response ratio (Wildeboer and Stevens, 2008). Tropisetron, a partial alpha7 agonist significantly improves gating in schizophrenia patients (Koike et al., 2005). Luntz-Leybman (Luntz-Leybman et al., 1992) showed that alpha-bungarotoxin, an alpha-7 nAChR antagonist, disrupts P20 and P40 gating in rats while mecamylamine showed no affect. Physiostigmine, a drug that deters the breakdown of endogenous cholinergic drug in the body by inhibiting acetylcholinesterase, normalizes P50 gating in a schizophrenia-free individual that exhibited gating deficits in the P50 gating, further supporting nicotine's role in modulating sensory gating (Adler et al., 1992). Direct pharmacological targeting of the nAChR directly is not necessarily the only way to trigger the receptors effects. In animal models, Siegel demonstrated that dopamine reuptake inhibition and nicotine antagonism both contribute to the observed phenotype of gating impairment in both the P20 and P40 gating in mice (Siegel et al., 2005). Nicotine and haloperidol increased P20 amplitude, supporting a role for nicotine agonists in pre-attentive sensory encoding deficits. While it remains elusive, the mechanism of action underlying the gating difference could be critical to understanding and treating the physiological

endophenotypes in regard to development of new therapies to target treatment-resistant

**Nicotine**. Nicotine has generated interest as a candidate for therapeutic use in alleviating schizophrenia symptoms. Individuals with schizophrenia are three times more likely to smoke and have high nicotine dependence compared to the general population (Hughes et al., 1986, de Leon and Diaz, 2005). They also have lower smoking cessation rates and selfadminister more nicotine during cigarette smoking than control patients, a finding supported by measuring cotinine, a nicotine metabolite used as a biomarker of tobacco exposure (Olincy et al., 1997, de Leon and Diaz, 2005). This, along with the known prevalence of genotype differences leading to the loss of function in the alpha 7 nicotinic receptor found in individuals with schizophrenia, (Adler et al., 1998, Leonard et al., 2001, Picciotto and Zoli, 2008) supports the idea that individuals with schizophrenia selfadminister nicotine as a form of self-medication to rectify deficits in neurocognitive performance and alleviate symptoms associated with the disease (Dalack and Meador-Woodruff, 1996, Kumari and Postma, 2005, Kumari et al., 2006)(Dalack and Meador-Woodruff, 1996).As mentioned previously, individuals with schizophrenia exhibit a higher ratio between the second and first stimulus in the auditory gating paradigm reflecting a dysfunction in stimulus processing. Acute nicotine in humans transiently normalizes the P50 gating deficit. This is observed with cigarette smoking in schizophrenia patients (Adler et al., 1993)as well as in studies using nicotine-containing gum in non-smoking family members of schizophrenia patients who exhibited P50 gating deficits (Adler et al., 1992). Mice undergoing 14 days of chronic nicotine increased both in the amplitude and gating of the P20, while having only acute nicotine decrease the amplitude and gating of N40(Metzger et al., 2007). A variety of pharmacological models further demonstrate the importance of the nAChr in stimulus gating. nAChR agonists display similar affects to nicotine. Acute administration of DMXB-A, a nicotinic agonist specifically targeting the alpha7 nicotinic, significantly suppressed the P50 of the test stimulus in subjects with schizophrenia, bringing the gating of the schizophrenia patients into the range of controls (Meyer et al., 1997, Olincy et al., 2006). These results were consistent with animal model studies testing the same drug(Stevens et al., 1998). Administration of 5-I A-85380, an alpha4beta2 nAChR agonist, in DBA/2 mice also significantly reduced the second to first stimulus response ratio (Wildeboer and Stevens, 2008). Tropisetron, a partial alpha7 agonist significantly improves gating in schizophrenia patients (Koike et al., 2005). Luntz-Leybman (Luntz-Leybman et al., 1992) showed that alpha-bungarotoxin, an alpha-7 nAChR antagonist, disrupts P20 and P40 gating in rats while mecamylamine showed no affect. Physiostigmine, a drug that deters the breakdown of endogenous cholinergic drug in the body by inhibiting acetylcholinesterase, normalizes P50 gating in a schizophrenia-free individual that exhibited gating deficits in the P50 gating, further supporting nicotine's role in modulating sensory gating (Adler et al., 1992). Direct pharmacological targeting of the nAChR directly is not necessarily the only way to trigger the receptors effects. In animal models, Siegel demonstrated that dopamine reuptake inhibition and nicotine antagonism both contribute to the observed phenotype of gating impairment in both the P20 and P40 gating in mice (Siegel et al., 2005). Nicotine and haloperidol increased P20 amplitude, supporting a role for nicotine agonists in pre-attentive sensory encoding deficits. While it remains elusive, the mechanism of action underlying the gating difference could be critical to understanding and treating the physiological

symptoms.

disturbances that cause the phenotype of schizophrenia, and nicotine is shown to affect this mechanism.

Since MMN deficits are thought to indicate degraded auditory perception experienced by schizophrenia patients, it follows that the effect of nicotine administration on schizophrenia symptoms be assessed using this measure. In the schizophrenia-free population, nicotine has been shown to enhance MMN amplitudes and shorten MMN latencies (Inami et al., 2005, Martin et al., 2009). Further evidence for the role of nicotine in ameliorating the MMN deficit emerges from the administration of the nicotinic agonist AZD3480, selective for the alpha-4-beta-2 subtype. As such, AZD3480 significantly increases the MMN amplitude and reduces the MMN latency, at the same time significantly enhancing scores in cognitive tests of attention and episodic memory when administered chronically for ten days (Dunbar et al., 2007). Human studies directly assessing the effects of nicotine on individuals with schizophrenia are few in number and exhibit mixed results. Acute nicotine transiently normalized the amplitude of MMN in response to duration but not frequency changes in auditory stimuli (Dulude et al., 2010). Inami found that acute transdermal nicotine in nonsmokers reduces the MMN latency in healthy subjects, but not in patients with schizophrenia (Inami et al., 2007). This finding could be unique to the schizophrenia population that refrains from smoking and may reflect either differential drives to smoke based on symptom alleviation or be affected by the myriad of neuronal adaptations that chronic nicotine exposure induces, creating two distinct populations in schizophrenia. More studies are needed to elucidate the role of nicotinic receptors on MMN performance. There are several issues that limit nicotine being used as therapeutic drug. The ubiquity of nicotine receptors in the CNS and PNS make it difficult for a drug to target a specific region of the brain. A therapeutic drug's binding specificity and route of administration would therefore have to be optimized so as to minimize drug side affects. Nicotine itself has a short half-life. The rapid metabolism of the drug and its transient effects would mean that a mechanism of sustained release would need to be employed for the agent to remain active for an extended period of time. However, a direct impediment to this therapeutic modification is that nicotinic receptors exhibit quick desensitization. This would mean target receptors might not be available for binding and drug efficacy. These factors must be addressed before nicotine can be seriously considered as a candidate as a therapeutic drug for schizophrenia patients. There are currently several drugs that act at the nAChR that show promise. Agonists like DMXBA have been shown to successfully overcome several of these pharmacological challenges and stand as contenders for therapeutic relief (Martin and Freedman, 2007). Other options include the use of a positive allosteric modulator to enhance the efficacy of the receptor without directly activating it (Gronlien et al., 2007).

#### **4.2.2 Transgenic approaches**

Schizophrenia carries an important genetic contribution with a heritability of approximately 80% (Sullivan et al., 2003). ERPs deficits, particularly of the P50, N100, P300 and MMN components are among the most heritable (approximately 70%) and reproducible phenotypes of schizophrenia (Frangou et al., 1997, Ahveninen et al., 2006, Hall et al., 2006, Turetsky et al., 2007a). Whereas the number of candidate genes for schizophrenia is estimated to be over 1000, a subset of specific genetic contributions have been directly associated with ERPs. These genes are mostly involved in dopaminergic, nicotinic and glutamatergic mechanisms. For example, P50 gating deficits have been linked to the alpha-7

Electrophysiological Deficits in Schizophrenia: Models and Mechanisms 43

*NR1 Tg mice*: NR1 hypomorphic mice express 5-10% of the normal NR1 protein (Mohn et al., 1999). Several studies have reported behavioral abnormalities in these mice that are also found in schizophrenia. Since then, NR1 hypomorphic mice have been considered as a translation model for the disease. Measure of auditory and visual event related potentials showed significant increased amplitudes of P20 and N40 in NR1 hypomorphic mice, suggesting decreased inhibitory tone (Bodarky et al., 2009, Halene et al., 2009). Indeed, auditory gating for the P20 and the N40 peak is significantly impaired in these mice compared to their wild-type littermates (Bickel et al., 2007, 2008). Those results correlate with the pathophysiology of the observed gating and ERPs generation alterations in

exhibit significant reduction of the alpha-7 nicotinic receptor in the hippocampus. In these mice, the auditory gating for P20 and N40 was decreased compare to the wild type mice. This result is consistent with the deficit of P50 gating reported for schizophrenia patients. These data reinforce the idea of a genetic linkage between the alpha-7 nicotinic receptor and

The notion that schizophrenia occurs as a result of problems in neurodevelopment is strongly suggested by the appearance of a number of gross alterations in the brain inn schizophrenia, including enlargement of the cerebral ventricles, decreased cortical volume, and hippocampal cellular pathology (Harrison, 1999). That these alterations have occurred early in development can be assumed given that they occur largely in areas of the brain, such as the hippocampus, that complete the developmental process long before the typical onset of the disease. Although the full emergence of schizophrenia symptoms usually does not occur until late-adolescence or early-adulthood, people who subsequently go on to develop schizophrenia often show numerous deficits in cognitive and social function indicative of problems early in the developmental process. Given the importance of identifying the potential mechanisms that underlie such developmental changes, numerous neurodevelopmental models have been proposed in animals that presume to replicate the

**NNVHL.** Lesioning of the ventral hippocampal area during early life has been shown to reproduce in rodents many of the symptoms observed in schizophrenia. Important features of this model are: 1) post-pubertal emergence of behavioral changes 2) schizophrenia-like deficits in cognition 3) schizophrenia-like changes on putative positive symptom measures, such as amphetamine-induced locomotor activity and pre-pulse inhibition 4) schizophrenia-like cellular and neuroanatomical changes, including reductions in parvalbumin expressing GABAergic interneurons 5) exaggerated response to glutamate agonist and antagonists, suggestive of a hypoglutamatergic state. Importantly, most of these changes occur only when the lesion is induced during the neonatal period and do not occur in adult animals given similar lesions of the ventral hippocampus, suggesting that it is the altered neurodevelopmental environment that is

**Methylazoxymethanol.** Embryonic exposure to methylazoxymethanol acetate (MAM), an inhibitor of cell division, is currently a popular animal model of schizophrenia. Exposure to MAM at embryonic day 17 produces a pattern of brain atrophy in adult animals similar

*7 Tg mice* (Adams et al., 2008)**:** C3Há7 null mutant heterozygote mice

schizophrenia (Javitt et al., 2000).

α

this phenotype observed in human.

**4.2.3 Environmental approaches**

conditions leading to schizophrenia-like brain dysfunction.

the source of the changes observed in the model.

**Nicotine.** *C3H*

nicotinic acetylcholine receptor as well as the Catechol-O-methyltransferase (COMT) genes (Lu et al., 2007), although the later result was not replicated in a recent study (Shaikh et al., , Freedman et al., 1997, Leonard et al., 1998, Shaikh et al., 2011). Also, P300 amplitude decrease is associated with COMT and Disrupted in schizophrenia-1 (DISC1) genes while P300 increased latency is significantly influenced by the dopamine D2/D3 receptor as well as the Neuregulin-1 (NRG1) genes (Hill et al., 1998, Anokhin et al., 1999, Blackwood et al., 2001, Gallinat et al., 2003, Blackwood and Muir, 2004, Berman et al., 2006, Mulert et al., 2006, Bramon et al., 2008). Finally, whereas MMN is most extensively investigated in regard to glutamatergic mechanisms, no study has genetically linked both. However, a genetic association between MMN and the COMT gene has been shown (Baker et al., 2005). Those reports, combined with the aforementioned pharmacological studies, demonstrate the importance of investigating ERPs in specific transgenic (Tg) mouse models of schizophrenia. To date, the Tg mouse models that have been used to study ERPs components can be separated in 3 main groups based on the molecular pathway in which the target gene is involved: 1) Dopamine (COMT and Gsa Tg mice), 2) glutamate (NRG1 and NMDA receptor-1 (NR1)) Tg mice and 3) nicotine (C3Hα7 receptor Tg mice).

**Dopamine.** *COMT Tg mice:* The Catechol-O-methyltransferase (COMT) is a key regulatory enzyme that degrades dopamine and thus controls dopamine availability (Axelrod and Tomchick, 1958, Goldberg and Weinberger, 2004). In humans, a single nucleotide polymorphism leads to the substitution of a Valine in place of a Methionine at the 158/108 locus (Lachman et al., 1996). This modification results in a two-fold increase of its activity thereby reducing dopamine levels (Chen et al., 2004). A recent study from our laboratory using COMT-Val-tg mice (Papaleo et al., 2008) shows a lack of change in P20 amplitude but a trend of P20 latency increase (unpublished data). These results are consistent with the human data mentioned above, which show both significant and non-significant genetic linkage between the COMT gene and P50 gating deficits. We also observed increased N40 latency and decreased P80 amplitude as well as reduced baseline theta and gamma power.

*Gsa Tg mice:* Gsa Tg mice express an isoform of the G-protein subunit Gsa that is constitutively active due to a point mutation (Q227L) that prevents hydrolysis of bound GTP (Wand et al., 2001, Gould et al., 2004). Gsa Tg mice displayed decreased amplitude of cortically-generated N40 that is reversed by the Gi-coupled dopamine D2-receptor antagonist haloperidol (Maxwell et al., 2006b). This result is consistent with the amplitude reduction of the N100 observed in patients with schizophrenia (Frangou et al., 1997, Ahveninen et al., 2006).

**Glutamate.** *NRG1 Tg mice:* NRG-1 is a high-risk gene for schizophrenia that has been associated with NMDA receptor hypofunction (Gu et al., 2005, Hahn et al., 2006, Bjarnadottir et al., 2007, Li et al., 2007). Although several Tg mice for NRG1 have been engineered, to our knowledge, only one study has tested auditory ERPs (Ehrlichman et al., 2009b). This study has used the NRG1 model in which all three major types of NRG1 have a partial deletion of the EGF like domain. These NRG1 heterozygote mice did not show deficits in P20 amplitude or gating. Nevertheless, they showed disrupted mismatch negativity similar to what is observed in schizophrenia. It would be interesting to investigate ERPs in the other NRG1 Tg mouse lines as it may help to identify which form of NRG1 mutant are most closely associated with the electrophysiological abnormalities commonly found in schizophrenia.

*NR1 Tg mice*: NR1 hypomorphic mice express 5-10% of the normal NR1 protein (Mohn et al., 1999). Several studies have reported behavioral abnormalities in these mice that are also found in schizophrenia. Since then, NR1 hypomorphic mice have been considered as a translation model for the disease. Measure of auditory and visual event related potentials showed significant increased amplitudes of P20 and N40 in NR1 hypomorphic mice, suggesting decreased inhibitory tone (Bodarky et al., 2009, Halene et al., 2009). Indeed, auditory gating for the P20 and the N40 peak is significantly impaired in these mice compared to their wild-type littermates (Bickel et al., 2007, 2008). Those results correlate with the pathophysiology of the observed gating and ERPs generation alterations in schizophrenia (Javitt et al., 2000).

**Nicotine.** *C3H*α*7 Tg mice* (Adams et al., 2008)**:** C3Há7 null mutant heterozygote mice exhibit significant reduction of the alpha-7 nicotinic receptor in the hippocampus. In these mice, the auditory gating for P20 and N40 was decreased compare to the wild type mice. This result is consistent with the deficit of P50 gating reported for schizophrenia patients. These data reinforce the idea of a genetic linkage between the alpha-7 nicotinic receptor and this phenotype observed in human.

#### **4.2.3 Environmental approaches**

42 Psychiatric Disorders – Trends and Developments

nicotinic acetylcholine receptor as well as the Catechol-O-methyltransferase (COMT) genes (Lu et al., 2007), although the later result was not replicated in a recent study (Shaikh et al., , Freedman et al., 1997, Leonard et al., 1998, Shaikh et al., 2011). Also, P300 amplitude decrease is associated with COMT and Disrupted in schizophrenia-1 (DISC1) genes while P300 increased latency is significantly influenced by the dopamine D2/D3 receptor as well as the Neuregulin-1 (NRG1) genes (Hill et al., 1998, Anokhin et al., 1999, Blackwood et al., 2001, Gallinat et al., 2003, Blackwood and Muir, 2004, Berman et al., 2006, Mulert et al., 2006, Bramon et al., 2008). Finally, whereas MMN is most extensively investigated in regard to glutamatergic mechanisms, no study has genetically linked both. However, a genetic association between MMN and the COMT gene has been shown (Baker et al., 2005). Those reports, combined with the aforementioned pharmacological studies, demonstrate the importance of investigating ERPs in specific transgenic (Tg) mouse models of schizophrenia. To date, the Tg mouse models that have been used to study ERPs components can be separated in 3 main groups based on the molecular pathway in which the target gene is involved: 1) Dopamine (COMT and Gsa Tg mice), 2) glutamate (NRG1 and NMDA

**Dopamine.** *COMT Tg mice:* The Catechol-O-methyltransferase (COMT) is a key regulatory enzyme that degrades dopamine and thus controls dopamine availability (Axelrod and Tomchick, 1958, Goldberg and Weinberger, 2004). In humans, a single nucleotide polymorphism leads to the substitution of a Valine in place of a Methionine at the 158/108 locus (Lachman et al., 1996). This modification results in a two-fold increase of its activity thereby reducing dopamine levels (Chen et al., 2004). A recent study from our laboratory using COMT-Val-tg mice (Papaleo et al., 2008) shows a lack of change in P20 amplitude but a trend of P20 latency increase (unpublished data). These results are consistent with the human data mentioned above, which show both significant and non-significant genetic linkage between the COMT gene and P50 gating deficits. We also observed increased N40 latency and decreased P80 amplitude as well as reduced baseline theta and gamma power. *Gsa Tg mice:* Gsa Tg mice express an isoform of the G-protein subunit Gsa that is constitutively active due to a point mutation (Q227L) that prevents hydrolysis of bound GTP (Wand et al., 2001, Gould et al., 2004). Gsa Tg mice displayed decreased amplitude of cortically-generated N40 that is reversed by the Gi-coupled dopamine D2-receptor antagonist haloperidol (Maxwell et al., 2006b). This result is consistent with the amplitude reduction of the N100 observed in patients with schizophrenia (Frangou et al., 1997,

**Glutamate.** *NRG1 Tg mice:* NRG-1 is a high-risk gene for schizophrenia that has been associated with NMDA receptor hypofunction (Gu et al., 2005, Hahn et al., 2006, Bjarnadottir et al., 2007, Li et al., 2007). Although several Tg mice for NRG1 have been engineered, to our knowledge, only one study has tested auditory ERPs (Ehrlichman et al., 2009b). This study has used the NRG1 model in which all three major types of NRG1 have a partial deletion of the EGF like domain. These NRG1 heterozygote mice did not show deficits in P20 amplitude or gating. Nevertheless, they showed disrupted mismatch negativity similar to what is observed in schizophrenia. It would be interesting to investigate ERPs in the other NRG1 Tg mouse lines as it may help to identify which form of NRG1 mutant are most closely associated with the electrophysiological abnormalities

receptor-1 (NR1)) Tg mice and 3) nicotine (C3Hα7 receptor Tg mice).

Ahveninen et al., 2006).

commonly found in schizophrenia.

The notion that schizophrenia occurs as a result of problems in neurodevelopment is strongly suggested by the appearance of a number of gross alterations in the brain inn schizophrenia, including enlargement of the cerebral ventricles, decreased cortical volume, and hippocampal cellular pathology (Harrison, 1999). That these alterations have occurred early in development can be assumed given that they occur largely in areas of the brain, such as the hippocampus, that complete the developmental process long before the typical onset of the disease. Although the full emergence of schizophrenia symptoms usually does not occur until late-adolescence or early-adulthood, people who subsequently go on to develop schizophrenia often show numerous deficits in cognitive and social function indicative of problems early in the developmental process. Given the importance of identifying the potential mechanisms that underlie such developmental changes, numerous neurodevelopmental models have been proposed in animals that presume to replicate the conditions leading to schizophrenia-like brain dysfunction.

**NNVHL.** Lesioning of the ventral hippocampal area during early life has been shown to reproduce in rodents many of the symptoms observed in schizophrenia. Important features of this model are: 1) post-pubertal emergence of behavioral changes 2) schizophrenia-like deficits in cognition 3) schizophrenia-like changes on putative positive symptom measures, such as amphetamine-induced locomotor activity and pre-pulse inhibition 4) schizophrenia-like cellular and neuroanatomical changes, including reductions in parvalbumin expressing GABAergic interneurons 5) exaggerated response to glutamate agonist and antagonists, suggestive of a hypoglutamatergic state. Importantly, most of these changes occur only when the lesion is induced during the neonatal period and do not occur in adult animals given similar lesions of the ventral hippocampus, suggesting that it is the altered neurodevelopmental environment that is the source of the changes observed in the model.

**Methylazoxymethanol.** Embryonic exposure to methylazoxymethanol acetate (MAM), an inhibitor of cell division, is currently a popular animal model of schizophrenia. Exposure to MAM at embryonic day 17 produces a pattern of brain atrophy in adult animals similar

Electrophysiological Deficits in Schizophrenia: Models and Mechanisms 45

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#### **4.3 Limitation and future models**

ERPs and ERSPs have been widely used to examine neural activity in normal individuals and those suffering from schizophrenia. The high degree of similarity between the methods used to assess these measures in humans and laboratory animals has made these techniques very valuable for studying normal and abnormal brain function. Presently, however, it is unclear how such measures relate to clinical symptoms or cognitive impairments, although evidence for a link between these measures and cognition is beginning to emerge. Future studies will need to assess the degree to which ERP and EEG measures relate to cognitive performance on tasks in mice that more closely replicate those used in humans. Establishment of such a link could provide a novel means for assessing cognition in mice and for testing potential pharmaceutical interventions for schizophrenia. Much work has been done assessing EEG during cognitive performance in humans, as well as in non-human primates, which has typically focused on sophisticated analyses of neural oscillations and synchrony. While such measures are interesting, ERP measures are also useful candidates for translational biomarkers of cognition, since they do not require extensive expertise to analyze and there are years of human data using these measures. Further, mice are excellent subjects for translational research, given the wide range of genetically modified mice available to researchers.

#### **5. References**

44 Psychiatric Disorders – Trends and Developments

to that seen in human schizophrenia (i.e. cortical and hippocampal atrophy) (Talamini et al., 1998). Importantly, these neural changes overlap with dysfunctions across a wide range of behavioral and cognitive domains known to be affected in humans with schizophrenia, including measures sensitive to mesolimbic dopamine function and cognitive performance. Thus, MAM treated animals display impaired long-term memory, working memory and attentional flexibility, as well as increased responsiveness to amphetamine as adults (Fiore et al., 2002, Gourevitch et al., 2004, Moore et al., 2006, Featherstone et al., 2007). The enhanced response to amphetamine is not seen when animals are tested during the pre-pubescent period, suggesting that the behavioral changes induced by MAM follow the same developmental time course seen in the human disease (Moore et al., 2006). Parvalbumin (PV) expressing GABAergic interneurons are dramatically reduced in both the hippocampus and PFC following embryonic MAM treatment, suggesting that these cells may be especially vulnerable to the effects of MAM. Moreover, it is possible that the loss of such cells could be responsible for many of the cognitive and behavioral changes that occur following MAM treatment (Penschuck et al., 2006). For example, PV expressing GABAergic interneurons are known to be the primary source of high frequency gamma oscillations. In a latent inhibition procedure, MAM treated animals showed reduced gamma power during pre-exposure to a tone and this was shown to correspond with impaired development of latent inhibition (Lodge et al., 2009). In contrast, exposure to MAM did not alter activity in the lower frequency theta band, suggesting a high degree of specificity in the underlying change induced by MAM treatment. Additionally, MAM treated animals show an enhanced locomotor response to NMDA antagonists such as ketamine and PCP, and this also appears to correspond strongly and specifically with a reduced ability for these drugs to alter activity within the gamma frequency range. Both studies suggest that MAM treatment results in a decreased inhibitory tone consistent with the proposed role of GABAergic interneurons in inhibitory

ERPs and ERSPs have been widely used to examine neural activity in normal individuals and those suffering from schizophrenia. The high degree of similarity between the methods used to assess these measures in humans and laboratory animals has made these techniques very valuable for studying normal and abnormal brain function. Presently, however, it is unclear how such measures relate to clinical symptoms or cognitive impairments, although evidence for a link between these measures and cognition is beginning to emerge. Future studies will need to assess the degree to which ERP and EEG measures relate to cognitive performance on tasks in mice that more closely replicate those used in humans. Establishment of such a link could provide a novel means for assessing cognition in mice and for testing potential pharmaceutical interventions for schizophrenia. Much work has been done assessing EEG during cognitive performance in humans, as well as in non-human primates, which has typically focused on sophisticated analyses of neural oscillations and synchrony. While such measures are interesting, ERP measures are also useful candidates for translational biomarkers of cognition, since they do not require extensive expertise to analyze and there are years of human data using these measures. Further, mice are excellent subjects for translational research, given the wide range of genetically modified mice

function.

**4.3 Limitation and future models**

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**3**

*Italy*

**State of Art of Serum Brain-Derived**

Davide Carlino1, Monica Baiano2,

Maurizio De Vanna1 and Enrico Tongiorgi3

*Technological and Tralsational Sciences, University of Trieste*

**Neurotrophic Factor in Schizophrenia**

*1Psychiatric Clinic, BRAIN Centre for Neuroscience, Department of Medical,*

*2Center for Weight and Eating Disorders – Veneto Orientale – Portogruaro (VE) 3BRAIN Centre for Neuroscience, Department of Life Sciences, University of Trieste*

Schizophrenia is a common severe psychiatric disorder which affects approximately 1% of the world population. Imaging studies and postmortem analysis have clearly shown that schizophrenia is not a mere functional disorder, but rather includes several histological abnormalities in various areas of the brain. Today, deficits in brain development or a malfunction in the dopaminergic system are considered the leading hallmarks of

Although the pathogenesis of schizophrenia remains still unresolved, it is now clear that this disorder is the result of a complex interplay between inheritable genetic mutations in a large number of genes (a few common mutations with a small effect combined with many rare ones with a stronger effect), various environmental influences and epigenetic effects (van OS & Kapur, 2009; Owen et al., 2009; O'Donnel et al., 2009; Psychiatric GWAS Consortium [PGC], 2009; Roth et al., 2009). Over the years, multiple theories have been proposed to explain how these factors may generate schizophrenia. The different models proposed include principally the neurodevelopmental and the dopaminergic hypotheses which have been reviewed elsewhere (Fatemi & Folsom, 2009; Howes & Kapur, 2009). These two hypotheses may not necessarily be mutually exclusive as, for instance, a local dysfunction in dopaminergic neurotransmission may be the result of a failed development. Moreover, a number of studies pointed to the role of neurotrophins in the pathogenesis of schizophrenia. Neurotrophins are a small group of secreted dimeric proteins that affect the development of the nervous system in all vertebrates' species and are involved in the development and maturation of several brain networks including the dopaminergic system (Buckley et al. 2007; Shoval & Weizman, 2005; Thome et al. 1998). Brain-Derived Neurotrophic Factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS) and is known to exert growth and trophic effects able to support many aspects of neuronal development including axonal growth and connectivity (Segal et al., 1995), neuronal survival and apoptosis (Segal et al., 1997), and formation of dopaminergic-related systems. Furthermore, BDNF has a dynamic effect on synaptic organization, promoting long-term

schizophrenia (Fatemi & Folsom, 2009; Howes & Kapur, 2009; Iritani, 2007).

**1. Introduction**

### **State of Art of Serum Brain-Derived Neurotrophic Factor in Schizophrenia**

Davide Carlino1, Monica Baiano2, Maurizio De Vanna1 and Enrico Tongiorgi3 *1Psychiatric Clinic, BRAIN Centre for Neuroscience, Department of Medical, Technological and Tralsational Sciences, University of Trieste 2Center for Weight and Eating Disorders – Veneto Orientale – Portogruaro (VE) 3BRAIN Centre for Neuroscience, Department of Life Sciences, University of Trieste Italy*

#### **1. Introduction**

66 Psychiatric Disorders – Trends and Developments

Yamamoto J (Cortical and hippocampal EEG power spectra in animal models of

Zouridakis G, Boutros NN (Stimulus parameter effects on the P50 evoked response.

Psychopharmacology 131:379-387.1997).

Biological psychiatry 32:839-841.1992).

schizophrenia produced with methamphetamine, cocaine, and phencyclidine.

Schizophrenia is a common severe psychiatric disorder which affects approximately 1% of the world population. Imaging studies and postmortem analysis have clearly shown that schizophrenia is not a mere functional disorder, but rather includes several histological abnormalities in various areas of the brain. Today, deficits in brain development or a malfunction in the dopaminergic system are considered the leading hallmarks of schizophrenia (Fatemi & Folsom, 2009; Howes & Kapur, 2009; Iritani, 2007).

Although the pathogenesis of schizophrenia remains still unresolved, it is now clear that this disorder is the result of a complex interplay between inheritable genetic mutations in a large number of genes (a few common mutations with a small effect combined with many rare ones with a stronger effect), various environmental influences and epigenetic effects (van OS & Kapur, 2009; Owen et al., 2009; O'Donnel et al., 2009; Psychiatric GWAS Consortium [PGC], 2009; Roth et al., 2009). Over the years, multiple theories have been proposed to explain how these factors may generate schizophrenia. The different models proposed include principally the neurodevelopmental and the dopaminergic hypotheses which have been reviewed elsewhere (Fatemi & Folsom, 2009; Howes & Kapur, 2009). These two hypotheses may not necessarily be mutually exclusive as, for instance, a local dysfunction in dopaminergic neurotransmission may be the result of a failed development. Moreover, a number of studies pointed to the role of neurotrophins in the pathogenesis of schizophrenia. Neurotrophins are a small group of secreted dimeric proteins that affect the development of the nervous system in all vertebrates' species and are involved in the development and maturation of several brain networks including the dopaminergic system (Buckley et al. 2007; Shoval & Weizman, 2005; Thome et al. 1998). Brain-Derived Neurotrophic Factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS) and is known to exert growth and trophic effects able to support many aspects of neuronal development including axonal growth and connectivity (Segal et al., 1995), neuronal survival and apoptosis (Segal et al., 1997), and formation of dopaminergic-related systems. Furthermore, BDNF has a dynamic effect on synaptic organization, promoting long-term

State of Art of Serum Brain-Derived Neurotrophic Factor in Schizophrenia 69

"BDNF" AND "schizophrenia". In addition, all reference lists of the selected papers were examined for studies not indexed electronically. The search aimed to find all papers published through January 2011.We used the PRISMA guidelines to carry out this review

**2.2 Inclusion/exclusion criteria for both the systematic review and meta-analysis**

schizoaffective or schizophreniform subjects were also considered.

1. Investigation of serum BNDF levels in patients with schizophrenia and healthy

3. Clinical characterization of patients with schizophrenia according to DSM-IV, ICD-10 or an equivalent system employed as a diagnostic tool. Study samples including some

1. Samples including non-schizophrenia psychosis or other schizophrenia spectrum

4. Patients or comparison subjects with neurological or medical disorders or substance or

In addition, in the studies exploring the same subject population or part of it, only the publication with the largest sample size was selected. When necessary, study Authors were

Each paper was scrutinized by two independent reviewers (D.C. and M.B.) separately, and the following data from the article was obtained: age, gender, education, age at onset, duration of illness, number of hospitalizations, medications used (type, dosage and duration of treatment) and laboratory parameters. Mean serum BDNF levels (expressed in ng/ml) and the methods used for statistical analyses were also extracted from the article. Furthermore, the reviewers rated the quality of each study using a modified version of the

1. Prospective evaluation of patients, use of specific diagnostic criteria and description of

2. Prospective evaluation of healthy control subjects, description of demographic data,

3. Presentation of significant variables (e.g. age, gender, age at onset, duration of illness,

1. Clear description of laboratory technique and measurements, such in a way to be

Studies had to fulfill the following inclusion criteria :

2. Mean serum BDNF reported (ng/ml or pg/ml).

3. Publications describing case reports or case series.

5. Comparison subjects screened for psychiatric disorders.

quality rating check-list reported on Baiano et al. (2007).

exclusion of psychiatric and medical illnesses;

number of hospitalizations, medications used);

2. Blindness of investigators to experimental setup; 3. Report of intra and inter-assay reliability;

Category 2: methods for sampling and analysis

contacted and asked to supply for missing or incomplete information.

2. Plasma BDNF levels were measured.

**2.3 Data abstraction and quality rating**

comparison subjects.

4. Published in English. Exclusion criteria comprised:

disorders.

alcohol abuse.

Category 1: subjects

reproducible;

demographic data;

(Figure 1).

changes of synaptic transmission (Shen et al., 1997), as well as learning and memory processes (Yamada et al., 2002). For these reasons many studies investigated the role of BDNF in the pathophysiology of schizophrenia but their findings resulted contradictory. For example, some postmortem studies conducted on schizophrenia brains showed elevated BDNF levels in the anterior cingulate, hippocampus (Takahashi et al., 2000) and cerebral cortex (Durany et al., 2001), whereas others found decreased BDNF levels in the hippocampus (Durany et al., 2001) and prefrontal cortex (Weickert et al., 2003, 2005).

Interestingly, in both humans and rodents, BDNF is present not only in the brain but also in peripheral tissues and especially, in the blood (Pruunsild et al., 2007; Aid et al., 2007). The origin of circulating BDNF has been debated as this neurotrophin is produced by many different body tissues and epithelia, including smooth muscle cells of blood vessels (Donovan et al., 1995). However, it has been demonstrated that radiolabeled BDNF injected in the jugular vein or in the brain ventricle readily crosses the blood-brain barrier in both directions (Pan et al., 1998) and can be taken up by platelets that function as storage and release system (Karege et al., 2005). In addition, it has been shown that physical exercise induces an increase of serum BDNF levels which is contributed by 70% from the brain (Rasmussen et al., 2009). Thus, measurement of circulating BDNF is very attractive, because it may provide information on brain functioning and blood samples are largely available and may be drawn non-invasively from living subjects as frequently as necessary. BDNF can be measured using simple enzyme linked immunoadsorbent assays (ELISA) that are commercially available and recent methodological studies have pointed out the possibility to obtain reliable measures of BDNF in serum preparations with stable values over several months of serum storage at -20°C, while in contrast, there is high variability in the measures of BDNF in whole blood or plasma because of the presence of release from platelets and degradation processes that are active even during storage (Elfving et al, 2009; Trajkovska et al., 2007). For these reasons, there is currently a great interest to validate the use of serum BDNF as possible biomarker in brain diseases, including psychiatric illnesses (for a recent meta-analisis of serum BDNF in depression see: Sen et al., 2008).

To assess if BDNF can represent a good biomarker in schizophrenia, a growing number of studies compared BDNF serum levels between patients with schizophrenia and healthy control subjects but unfortunately, with controversial results.  Because of these discrepancies, we decided to perform a systematic review and a meta-analysis of studies measuring serum concentrations of BDNF to elucidate whether or not this neurotrophin is abnormally produced in patients with schizophrenia. Additionally, we were interested in identifying factors that might contribute to the different findings in literature, as to improve the design of future investigations in this field.

#### **2. Methods**

#### **2.1 Search strategy**

The PUBMED, OVID MEDLINE, PSYCHINFO and EMBASE databases were searched using the following medical subject headings (MeSH): "Brain-Derived Neurotrophic Factor" OR "BDNF" AND "schizophrenia". In addition, all reference lists of the selected papers were examined for studies not indexed electronically. The search aimed to find all papers published through January 2011.We used the PRISMA guidelines to carry out this review (Figure 1).

#### **2.2 Inclusion/exclusion criteria for both the systematic review and meta-analysis**

Studies had to fulfill the following inclusion criteria :

68 Psychiatric Disorders – Trends and Developments

changes of synaptic transmission (Shen et al., 1997), as well as learning and memory processes (Yamada et al., 2002). For these reasons many studies investigated the role of BDNF in the pathophysiology of schizophrenia but their findings resulted contradictory. For example, some postmortem studies conducted on schizophrenia brains showed elevated BDNF levels in the anterior cingulate, hippocampus (Takahashi et al., 2000) and cerebral cortex (Durany et al., 2001), whereas others found decreased BDNF levels in the

Interestingly, in both humans and rodents, BDNF is present not only in the brain but also in peripheral tissues and especially, in the blood (Pruunsild et al., 2007; Aid et al., 2007). The origin of circulating BDNF has been debated as this neurotrophin is produced by many different body tissues and epithelia, including smooth muscle cells of blood vessels (Donovan et al., 1995). However, it has been demonstrated that radiolabeled BDNF injected in the jugular vein or in the brain ventricle readily crosses the blood-brain barrier in both directions (Pan et al., 1998) and can be taken up by platelets that function as storage and release system (Karege et al., 2005). In addition, it has been shown that physical exercise induces an increase of serum BDNF levels which is contributed by 70% from the brain (Rasmussen et al., 2009). Thus, measurement of circulating BDNF is very attractive, because it may provide information on brain functioning and blood samples are largely available and may be drawn non-invasively from living subjects as frequently as necessary. BDNF can be measured using simple enzyme linked immunoadsorbent assays (ELISA) that are commercially available and recent methodological studies have pointed out the possibility to obtain reliable measures of BDNF in serum preparations with stable values over several months of serum storage at -20°C, while in contrast, there is high variability in the measures of BDNF in whole blood or plasma because of the presence of release from platelets and degradation processes that are active even during storage (Elfving et al, 2009; Trajkovska et al., 2007). For these reasons, there is currently a great interest to validate the use of serum BDNF as possible biomarker in brain diseases, including psychiatric illnesses (for a recent

To assess if BDNF can represent a good biomarker in schizophrenia, a growing number of studies compared BDNF serum levels between patients with schizophrenia and healthy control subjects but unfortunately, with controversial results.  Because of these discrepancies, we decided to perform a systematic review and a meta-analysis of studies measuring serum concentrations of BDNF to elucidate whether or not this neurotrophin is abnormally produced in patients with schizophrenia. Additionally, we were interested in identifying factors that might contribute to the different findings in

The PUBMED, OVID MEDLINE, PSYCHINFO and EMBASE databases were searched using the following medical subject headings (MeSH): "Brain-Derived Neurotrophic Factor" OR

hippocampus (Durany et al., 2001) and prefrontal cortex (Weickert et al., 2003, 2005).

meta-analisis of serum BDNF in depression see: Sen et al., 2008).

literature, as to improve the design of future investigations in this field.

**2. Methods**

**2.1 Search strategy**

In addition, in the studies exploring the same subject population or part of it, only the publication with the largest sample size was selected. When necessary, study Authors were contacted and asked to supply for missing or incomplete information.

#### **2.3 Data abstraction and quality rating**

Each paper was scrutinized by two independent reviewers (D.C. and M.B.) separately, and the following data from the article was obtained: age, gender, education, age at onset, duration of illness, number of hospitalizations, medications used (type, dosage and duration of treatment) and laboratory parameters. Mean serum BDNF levels (expressed in ng/ml) and the methods used for statistical analyses were also extracted from the article. Furthermore, the reviewers rated the quality of each study using a modified version of the quality rating check-list reported on Baiano et al. (2007).

Category 1: subjects

Category 2: methods for sampling and analysis