Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic n-methyl-d-aspartate receptor (NMDAR) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder (MDD), although the underlying mechanism is unclear1-3. Depressed patients report alleviation of MDD symptoms within two hours of a single low-dose intravenous infusion of ketamine with effects lasting up to two weeks1-3, unlike traditional antidepressants (i.e. serotonin reuptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current MDD therapies, leaving a need for faster acting antidepressants particularly for suicide-risk patients3. Ketamine's ability to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. We show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models that depend on rapid synthesis of brain-derived neurotrophic factor (BDNF). We find that ketamine-mediated NMDAR blockade at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII) resulting in reduced eEF2 phosphorylation and desuppression of BDNF translation. Furthermore, we find inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings suggest that protein synthesis regulation by spontaneous neurotransmission may serve as a viable therapeutic target for fast-acting antidepressant development.

Learning and memory depend on the activity-dependent structural plasticity of synapses and changes in neuronal gene expression. We show that deletion of the MEF2C transcription factor in the CNS of mice impairs hippocampal-dependent learning and memory. Unexpectedly, these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission. Conversely, neuronal expression of a superactivating form of MEF2C results in a reduction of excitatory postsynaptic sites without affecting learning and memory performance. We conclude that MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampaldependent learning and memory.synaptic transmission ͉ synaptogenesis ͉ learning deficits N eurons process and retain information by forming synaptic connections that are modified by the intensity and frequency of their activity. The capacity to regulate the efficacy of synaptic transmission is essential for the continual remodeling of neural networks required for cognitive processes such as learning and memory. Distinct molecular mechanisms control synaptic plasticity associated with the different temporal stages of memory. A short-term process lasting minutes depends on modifications of preexisting proteins, whereas a long-term process lasting hours and days depends on changes in gene expression and protein synthesis (1).Originally identified as regulators of muscle development, members of the MEF2 (Myocyte Enhancer Factor 2) family of MADS (MCM1, agamous, deficiens, serum response factor) box transcription factors are expressed in overlapping but distinct regions of the CNS that correlate with the withdrawal of neurons from the cell cycle and acquisition of a differentiated phenotype (2). Mef2c is the first of four Mef2 genes to be expressed in the CNS and, in the adult brain, is highly expressed in the frontal cortex, entorhinal cortex, dentate gyrus, and amygdala (3, 4). RNA interference-mediated knockdown of MEF2A and MEF2D in cultured hippocampal neurons increases the number of excitatory synapses and the frequency of miniature excitatory postsynaptic currents (mEPSCs) (5). These alterations depend on the ability of the MEF2 proteins to stimulate neural activitydependent transcription of target genes (5). In contrast, loss of MEF2A in cerebellar granule neurons results in a decrease in the number of dendritic claws (6).Here, we present an analysis of the neuronal functions of the Mef2 gene in vivo. Through conditional deletion of Mef2c and expression of a superactive form of MEF2C in neurons of mice, we show that this MEF2 isoform plays an essential role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. ResultsBrain-Specific Deletion of MEF2C. We deleted Mef2c specifically in the CNS by breeding Mef2c loxP/loxP females (7) to Mef2c KO/ϩ heterozygous male (8) mice h...

These data suggest that the loss of hippocampal BDNF per se is not sufficient to mediate depression-like behavior. However, these results support the view that BDNF in the DG might be essential in mediating the therapeutic effect of antidepressants.

Synaptic vesicles in the brain harbor several SNARE proteins. With the exception of synaptobrevin2/VAMP2 (syb2) that is directly involved in vesicle fusion, the role of these SNAREs in neurotransmission is unclear. Here, we show that in mice while syb2 drives rapid Ca2+-dependent synchronous neurotransmission, the structurally homologous SNARE protein VAMP4 selectively maintains bulk Ca2+-dependent asynchronous release. At inhibitory nerve terminals, up- or down-regulation of VAMP4 causes a correlated change in asynchronous release. Biochemically, VAMP4 forms a stable complex with SNAREs syntaxin-1 and SNAP-25 that does not interact with complexins or synaptotagmin-1, proteins essential for synchronous neurotransmission. Optical imaging of individual synapses indicates that VAMP4 and syb2 trafficking show minimal overlap. Taken together, these findings suggest that VAMP4 and syb2 diverge functionally, traffic independently and support distinct forms of neurotransmission. These results provide molecular insight into how synapses diversify their release properties by taking advantage of distinct synaptic vesicle-associated SNAREs.

Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological histone deacetylase (HDAC) inhibitors, primarily those targeted to Class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of Class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual Class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.