 aggressive behaviors, the relevance of this measurement should be questioned. And contrary to the authors discussion point, the use of antipsychotics in fact was reported to disrupt nesting behavior (Li et al., 2004).
There were no differences between knockouts and wild-type mice in terms of their balance and coordination, but knockouts did show increased anxiety in the open field test. Further tests, perhaps using the elevated plus maze, would be required to confirm the anxiogenic effect. Interestingly, even though male and female knockout mice were generated for this study, with the exception of the results for the PPI, nesting, and aggression tests, there was no specific mention as to whether there were any sex-specific differences for the other tests.
In terms of the neuromolecular findings, in the PSD the loss of densin produced a decrease in the level of DISC1 and mGluR5 in the forebrain regions of knockouts, which led the authors to propose the existence of a multiprotein complex of densin, DISC1, and mGluR5. Specifically in the context of schizophrenia, reductions in the expression of DISC1 have been previously reported (Brandon et al., 2009), and there have been rodent models based on mGluR5-hypofunction (Gray et al., 2009). Secondly, there were no effects on CaMKII, SynGAP, or PSD-95 in the PSD. PSD-95 in particular is involved in the trafficking of NMDA receptors (NMDARs). The NMDA receptor hypofunction hypothesis of schizophrenia posits that a reduction in glutamatergic neurotransmission is a key feature and cause of the behavioral phenotype. The deletion of densin has no effect on ionotrophic glutamate receptor expression or localization in the PSD, and, hence, the knockouts would be expected to show normal neurotransmission, and indeed this is what the authors found. So it would be appropriate to conclude that this model does not display the construct validity normally associated with the glutamate hypothesis. Furthermore, from a technical point of view, the analysis of entire forebrain regions of the knockouts may miss out on regionally specific effects of densin deletion which may or may not have been important.
The authors went on to discover that in double knockouts of both densin and NMDARs (GluN1), there was reduced colocalization of CaMKII with PSD-95 in the PSD (~50 percent) compared to NMDAR knockouts alone (~15 percent), even though there was no effect on PSD-95 expression itself. This led the authors to suggest that if either densin or the NMDAR is missing, there is a partial docking of CaMKII together with PSD-95, but if both are missing, there is much less colocalization. The authors then hypothesized that in densin knockouts, CaMKII would bind more to NMDARs as a compensatory response, and, in turn, this would enhance glutamatergic neurotransmission. They found that, while basal CaMKII activity was lower in knockouts, in the presence of the GABAA antagonist bicuculline, phosphorylation of CaMKII was double that observed in wild-types. The authors concluded based on this finding that even though the deletion of densin appears to have no direct impact on the level of expression or localization of CaMKII within the PSD, there are indirect consequences on its localization with respect to other PSD components, and this in turn affects its basal activity and how it responds to neuronal stimuli.
These densin-related changes in PSD architecture and function were thought to result in effects on synaptic plasticity in hippocampal preparations, but this was limited only to LTD. The application of low-frequency stimulation or the application of an mGluR agonist, DHPG, induced no LTD in the knockouts compared to the wild-types. As the authors suggest, the deletion of densin impairs a biochemical step from the point of receptor activation (NMDAR or mGluR5), but to determine whether this was related to the reduced CaMKII microlocalization with PSD-95, the authors could have performed another experiment with the use of the CaMKII inhibitor KN-62, which is known to facilitate DHPG-induced LTD (Schnabel et al., 1999). DHPG is an mGluR1 and mGluR5 receptor agonist, so it could also be suggested that the densin-related decrease in mGluR5 expression in the PSD is not offset by a compensatory increase in mGluR1-receptor activity. It was not reported whether there was any effect of densin deletion on mGluR1 expression in the PSD.
In terms of hippocampal dendritic spine morphology, the loss of densin did not result in any significant changes in overall spine density, but there were significant effects on mushroom spine length (longer) and spine neck diameter (thinner). Bigger, voluminous headed spines are believed to have a greater PSD area, and hence are stronger synaptic contact points. In this study, the average spine head volume as calculated using the diameter seems unaffected by densin loss in all three types (mushroom, stubby, and thin). Strictly speaking, however, the association between spine morphology and psychiatric illness is weak and difficult to interpret given the highly plastic nature of their shape, and that it is often unclear whether changes are due to a primary cause or a downstream effect (Nimchinsky et al., 2002).
Overall, densin-180 knockout mice do show some behavioral changes which resemble some of the positive and negative symptoms of schizophrenia, but future studies would be necessary to confirm the findings using more specific testing paradigms and alternative protocols. To their credit, the authors have done a tremendous amount of work to produce the results, but no attempt was made to make a link between the molecular and behavioral changes. Unfortunately, this "missing link" is what many in the field would describe as a significant limitation of this animal model.
References:
Brandon NJ, Millar JK, Korth C, Sive H, Singh KK, Sawa A (2009) Understanding the role of DISC1 in psychiatric disease and during normal development. J Neurosci 29:12768-12775. (2011) Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction. J Neurosci 31:16194-16207. Abstract
Csomor PA, Yee BK, Vollenweider FX, Feldon J, Nicolet T, Quednow BB (2008) On the influence of baseline startle reactivity on the indexation of prepulse inhibition. Behav Neurosci 122:885-900. Abstract. Abstract
Li M, Davidson P, Budin R, Kapur S, Fleming AS (2004) Effects of typical and atypical antipsychotic drugs on maternal behavior in postpartum female rats. Schizophr Res 70:69-80. Abstract
Nimchinsky EA, Sabatini BL, Svoboda K (2002) Structure and Function of Dendritic Spines. Annual Review of Physiology 64:313-353. Abstract
Schnabel R, Palmer MJ, Kilpatrick IC, Collingridge GL (1999) A CaMKII inhibitor, KN-62, facilitates DHPG-induced LTD in the CA1 region of the hippocampus. Neuropharmacology 38:605-608. Abstract
PRIMARY PAPERSStructure and evolutionary history of DISC1.Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction.NMDA receptor regulates migration of newly generated neurons in the adult hippocampus via Disrupted-In-Schizophrenia 1 (DISC1).DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway.Expression of mutant human DISC1 in mice supports abnormalities in differentiation of oligodendrocytes.Genetic and functional analyses identify DISC1 as a novel callosal agenesis candidate gene.Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice.PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1.Disc1 regulates both ß-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis.Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse.
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