is involved in ltd induction in the prefrontal cortex (pfc). the serotonin system in the pfc plays an important role in regulating cognition and emotion. serotonin, in cooperation with a group i metabotropic glutamate receptor (mglur) agonist, facilitates ltd induction through augmentation of ampa receptor internalization. this mechanism possibly underlies serotonin's role in the control of cognitive and emotional processes that synaptic plasticity in pfc neurons mediates. perirhinal cortex computational models predict that ltd creates a gain in recognition memory storage capacity over that of ltp in the perirhinal cortex, and this prediction is confirmed by neurotransmitter receptor blocking experiments. it is proposed that there are multiple memory mechanisms in the perirhinal cortex. the exact mechanisms are not completely understood, however pieces of the mechanisms have been deciphered. studies suggest that one perirhinal cortex ltd mechanism involves nmda receptors and group i and ii mglu receptors 24 hours after the stimulus. the other ltd mechanism involves acetylcholine receptors and kainate receptors at a much earlier time, about 20 to 30 minutes after stimulus. role of endocannabinoids endocannabinoids affect long-lasting plasticity processes in various parts of the brain, serving both as regulators of pathways and necessary retrograde messengers in specific forms of ltd. in regard to retrograde signaling, cannabinoid receptors function widely throughout the brain in presynaptic inhibition. endocannabinoid retrograde signaling has been shown to effect ltd at corticostriatal synapses and glutamatergic synapses in the prelimbic cortex of the nucleus accumbens (nac), and it is also involved in spike-timing-dependent ltd in the visual cortex. endocannabinoids are implicated in ltd of inhibitory inputs (ltdi) within the basolateral nucleus of the amygdala (bla) as well as in the stratum radiatum of the hippocampus. additionally, endocannabinoids play an important role in regulating various forms of synaptic plasticity. they are involved in inhibition of ltd at parallel fiber purkinje neuron synapses in the cerebellum and nmda receptor-dependent ltd in the hippocampus. spike timing-dependent plasticity spike timing-dependent plasticity (stdp) refers to the timing of presynaptic and postsynaptic action potentials. stdp is a form of neuroplasticity in which a millisecond-scale change in the timing of presynaptic and postsynaptic spikes will cause differences in postsynaptic ca2+ signals, inducing either ltp or ltd. ltd occurs when postsynaptic spikes precede presynaptic spikes by up to 20-50 ms. whole-cell patch clamp experiments "in vivo" indicate that post-leading-pre spike delays elicit synaptic depression. ltp is induced when neurotransmitter release occurs 5-15 ms before a back-propagating action potential, whereas ltd is induced when the stimulus occurs 5-15 ms after the back-propagating action potential. there is a plasticity window: if the presynaptic and postsynaptic spikes are too far apart (i.e., more than 15 ms apart), there is little chance of plasticity. the possible window for ltd is wider than that for ltp – although it is important to note that this threshold depends on synaptic history. when postsynaptic action potential firing occurs prior to presynaptic afferent firing, both presynaptic endocannabinoid (cb1) receptors and nmda receptors are stimulated at the same time. postsynaptic spiking alleviates the mg2+ block on nmda receptors. the postsynaptic depolarization will subside by the time an epsp occurs, enabling mg2+ to return to its inhibitory binding site. thus, the influx of ca2+ in the postsynaptic cell is reduced. cb1 receptors detect postsynaptic activity levels via retrograde endocannabinoid release. stdp selectively enhances and consolidates specific synaptic modifications (signals), while depressing global ones (noise). this results in a sharpened signal-to-noise ratio in human cortical networks that facilitates the detection of relevant signals during information processing in humans. motor learning and memory long-term depression has long been hypothesized to be an important mechanism behind motor learning and memory. cerebellar ltd is thought to lead to motor learning, and hippocampal ltd is thought to contribute to the decay of memory. however, recent studies have found that hippocampal ltd may not act as the reverse of ltp, but may instead contribute to spatial memory formation. although ltd is now well characterized, these hypotheses about its contribution to motor learning and memory remain controversial. studies have connected deficient cerebellar ltd with impaired motor learning. in one study, metabotropic glutamate receptor 1 mutant mice maintained a normal cerebellar anatomy but had weak ltd and consequently impaired motor learning. however the relationship between cerebellar ltd and motor learning has been seriously challenged. a study on rats and mice proved that normal motor learning occurs while ltd of purkinje cells is prevented by (1r-1-benzo thiophen-5-yl-2 ethanol hydrochloride (t-588). likewise, ltd in mice was disrupted using several experimental techniques with no observable deficits in motor learning or performance. these taken together suggest that the correlation between cerebellar ltd and motor learning may have been illusory. studies on rats have made a connection between ltd in the hippocampus and memory. in one study, rats were exposed to a novel environment, and homosynaptic plasticity (ltd) in ca1 was observed. after the rats were brought back to their initial environment, ltd activity was lost. it was found that if the rats were exposed to novelty, the electrical stimulation required to depress synaptic transmission was of lower frequency than without novelty. when the rat was put in a novel environment, acetylcholine was released in the hippocampus from the medial septum fiber, resulting in ltd in ca1. therefore, it has been concluded that acetylcholine facilitates ltd in ca1. ltd has been correlated with spatial learning in rats, and it is crucial in forming a complete spatial map. it suggested that ltd and ltp work together to encode different aspects of spatial memory. new evidence suggests that ltp works to encode space, whereas ltd works to encode the features of space. specifically, it is accepted that encoding of experience takes place on a hierarchy. encoding of new space is the priority of ltp, while information about orientation in space could be encoded by ltd in the dentate gyrus, and the finer details of space could be encoded by ltd in the ca1. cocaine as a model of ltd in drug addiction the addictive property of cocaine is believed to occur in the nucleus accumbens (nac). after chronic cocaine use, the amount of ampa receptors relative to nmda receptors decreases in the medium spiny neurons in the nac shell. this decrease in ampa receptors is thought to occur through the same mechanism as nmdar-dependent ltd, because this form of plasticity is reduced after cocaine use. after, the amount of ampa receptors is ramped up in the nac neurons during withdrawal. this is possibly due to homeostatic synaptic scaling. this increase in ampa receptors causes a hyperexcitability in the nac neurons (gabaergic msns). this leads to an increase of gaba release by projections from the nac to the ventral tegmental area (vta), making the dopaminergic neurons in the vta less likely to fire, and thus resulting in the symptoms of withdrawal. current research research on the role of ltd in neurological disorders such as alzheimer's disease (ad) is ongoing. it has been suggested that a reduction in nmdar-dependent ltd may be due to changes not only in postsynaptic ampars but also in nmdars, and these changes are perhaps present in early and mild forms of alzheimer-type dementia. additionally, researchers have recently discovered a new mechanism (which involves ltd) linking soluble amyloid beta protein (aβ) with the synaptic injury and memory loss related to ad. while aβ's role in ltd regulation has not been clearly understood, it has been found that soluble aβ facilitates hippocampal ltd and is mediated by a decrease in glutamate recycling at hippocampal synapses. excess glutamate is a proposed contributor to the progressive neuronal loss involved in ad. evidence that soluble aβ enhances ltd through a mechanism involving altered glutamate uptake at hippocampal synapses has important implications for the initiation of synaptic failure in ad and in types of age-related aβ accumulation. this research provides a novel understanding of the development of ad and proposes potential therapeutic targets for the disease. further research is needed to understand how soluble amyloid beta protein specifically interferes with glutamate transporters. in the field of research of cerebellum disorders, auto-antigens are involved in molecular cascades for induction of ltd of synaptic transmissions between parallel fibers (pfs) and purkinje cells (pcs), a mechanism of synaptic plasticity in the cerebellum. anti-vgcc, anti-mglur1, and anti-glur delta abs-associated cerebellar ataxias share one common pathophysiological mechanism: a deregulation in pf-pc ltd. this causes an impairment of restoration or maintenance of the internal model hold by the cerebellum and triggers cerebellar ataxias. these diseases are ltdpathies. the mechanism of long-term depression has been well characterized in limited parts of the brain. however, the way in which ltd affects motor learning and memory is still not well understood. determining this relationship is presently one of the major focuses of ltd research. neurodegeneration neurodegenerative diseases research remains inconclusive as to the mechanisms that triggers the degeneration in the brain. new evidence demonstrates there are similarities between the apoptotic pathway and ltd which involves the phosphorylation/activation of gsk3β. nmdar-ltd(a) contributes to the elimination of excess synapses during development. this process is downregulated after synapses have stabilized, and is regulated by gsk3β. during neurodegeneration, there is the possibility that there is deregulation of gsk3β resulting in 'synaptic pruning'. if there is excess removal of synapses, this illustrates early signs of neurodegeration and a link between apoptosis and neurodegeneration diseases.