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.

Background Identifying and understanding reasons for being unsure or unwilling regarding intention to be vaccinated against coronavirus disease (COVID-19) may help to inform future public health messages aimed at increasing vaccination coverage. We analyzed a broad array of individual's psychological dispositions with regard to decision-making about COVID-19 vaccination in Japan. Methods A nationally representative cross-sectional web survey was conducted with 30053 Japanese adults aged 20 years or older at the end of February 2021. In addition to the question on the individual's intention to be vaccinated against COVID-19, respondents were asked about their sociodemographic, health-related, and psychological characteristics as well as information sources about COVID-19 and their levels of trust. Also, those who responded ‘not sure’ or ‘no’ regarding intention to take COVID-19 vaccine were asked why. Multinomial logistic regression with sparse group Lasso (Least Absolute Shrinkage and Selection Operator) penalty was used to compute adjusted odds ratios for factors associated with the intention (not sure/no versus yes). Findings The percentages of respondents who answered ‘not sure’ or ‘no’ regarding intention to be vaccinated against COVID-19 vaccine were 32.9% and 11.0%, respectively. After adjusting for covariates, the perceived risks of COVID-19, perceived risk of a COVID-19 vaccine, perceived benefits of a COVID-19 vaccine, trust in scientists and public authorities, and the belief that healthcare workers should be vaccinated were significantly associated with vaccination intention. Several sources of information about COVID-19 were also significantly associated with vaccination intention, including physicians, nurses, and television, medical information sites with lower odds of being unsure or unwilling, and internet news sites, YouTube, family members, and scientists and researchers with higher odds. The higher the level of trust in television as a source of COVID-19 information, the higher the odds of responding ‘not sure’ (odds ratio 1.11, 95% confidence interval 1.01–1.21). We also demonstrated that many respondents presented concerns about the side effects and safety of a COVID-19 vaccine as a major reason for being unsure or unwilling. To decide whether or not to get the vaccine, many respondents requested more information about the compatibilities between the vaccine and their personal health conditions, whether other people had been vaccinated, the effectiveness of vaccines against variants, and doctors’ recommendations. Interpretation Our findings suggest that public health messaging based on the sociodemographic and psychological characteristics of those who are unsure or unwilling regarding intention to be vaccinated against COVID-19 vaccine may help to increase vaccine uptake amongst this population. Funding The present work was supported in part by a grant from the...

Rett syndrome and MECP2 duplication syndrome are neurodevelopmental disorders that arise from loss of function and gain of function alterations in Methyl-CpG Binding Protein 2 (MeCP2) expression, respectively. Although there have been studies examining MeCP2 loss of function in animal models, there is limited information on MeCP2 overexpression in animal models. Here, we characterize a mouse line with MeCP2 overexpression restricted to neurons (Tau-Mecp2). This MeCP2 overexpression line shows motor coordination deficits, heightened anxiety, and impairments in learning and memory that are accompanied by deficits in long-term potentiation and short-term synaptic plasticity. Whole cell voltage clamp recordings of cultured hippocampal neurons from Tau-Mecp2 mice reveal augmented frequency of miniature excitatory postsynaptic currents with no change in miniature inhibitory postsynaptic currents indicating that overexpression of MeCP2 selectively impacts excitatory synapse function. Moreover, we show that alterations in transcriptional repression mechanisms underlie the synaptic phenotypes in hippocampal neurons from the Tau-Mecp2 mice. These results demonstrate the Tau-Mecp2 mouse line recapitulates many key phenotypes of MECP2 duplication syndrome and support the use of these mice to further study this devastating disorder.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that results from loss of function mutations in the methyl-CpG binding protein 2 (MECP2) gene. Using viral-mediated basolateral amygdala (BLA)-specific deletion of Mecp2 in mice, we show that intact Mecp2 function is required for normal anxiety behavior as well as some types of learning and memory. To examine whether these behavioral deficits are the result of impaired transcriptional repression, because Mecp2 is believed to act as a transcriptional repressor in complex with histone deacetylases (HDACs), we infused a HDAC inhibitor chronically into the BLA of wild-type mice. We found that HDAC inhibition produces behavioral deficits similar to those observed after the deletion of Mecp2 in the BLA. These results suggest a key role for Mecp2 as a transcriptional repressor in the BLA in mediating behavioral features of RTT.