Bipolar disorder, characterized by extreme manic and depressive moods, is a prevalent debilitating disease of unknown etiology. Because mood stabilizers, antipsychotics, antidepressants, and mood-regulating neuromodulators increase the inhibitory serine-phosphorylation of glycogen synthase kinase-3 (GSK3), we hypothesized that deficient GSK3 serine-phosphorylation may increase vulnerability to mood-related behavioral disturbances. This was tested by measuring behavioral characteristics of GSK3α/β21A/21A/9A/9A knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3. GSK3 knockin mice displayed increased susceptibility to amphetamine-induced hyperactivity and to stress-induced depressive-like behaviors. Furthermore, serine-phosphorylation of GSK3 was reduced during both mood-related behavioral responses in wild-type mouse brain and in blood cells from patients with bipolar disorder. Therefore, proper control of GSK3 by serine-phosphorylation, which is targeted by agents therapeutic for bipolar disorder, is an important mechanism that regulates mood stabilization, and mice with disabled GSK3 serine-phosphorylation may provide a valuable model to study bipolar disorder.

Elevated levels of estradiol enhance learning in mammals, including humans, likely a result of hormone-induced heightened plasticity at CA3-CA1 synapses. The increase in long-term potentiation (LTP) magnitude is considered to be a consequence of the estradiol-induced increase in dendritic spine density and NMDA receptor (NMDAR)-mediated transmission; however, direct evidence linking these changes together is lacking. Alternatively, alterations in GABAergic inhibition or presynaptic release probability could contribute. Here, we show in time course studies using hippocampal slices from estradiol-treated ovariectomized rats that the LTP magnitude is increased only when spine density is increased simultaneously with an increase in NMDAR transmission relative to AMPA receptor (AMPAR) transmission, with no role for alterations in GABAergic inhibition or release probability. With time after hormone treatment, AMPAR transmission gradually increases during the maintained increase in spine density and NMDAR transmission. Eventually, the balance between NMDAR and AMPAR transmission is reestablished, and the LTP magnitude is no longer increased. Blocking genomic estrogen receptors prevents the heightened spine density, NMDAR transmission, and LTP magnitude, suggesting a tight mechanistic coupling between these morphological and functional changes. Thus, we propose that the hormone-induced increase in functional synapse density alone is not sufficient to support heightened plasticity. Rather, estradiol increases LTP via enhancing NMDAR transmission, likely through receptor insertion into newly formed or preexisting synapses. Later, when excitability in the circuit is at its highest and spine density remains elevated, the LTP magnitude is no longer increased, probably as a consequence of the delayed increase in AMPAR transmission that resets the balance between NMDAR and AMPAR transmission.

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Learning triggers alterations in gene transcription in brain regions such as the hippocampus and the entorhinal cortex (EC) that are necessary for long-term memory (LTM) formation. Here, we identify an essential role for the G9a/GLP lysine dimethyltransferase complex and the histone H3 lysine 9 di-methylation (H3K9me2) marks it catalyzes, in the transcriptional regulation of genes in area CA1 of the rat hippocampus and the EC during memory consolidation. Contextual fear learning increased global levels of H3K9me2 in area CA1 and the EC, with observable changes at the Zif268, DNMT3a, BDNF exon IV, and cFOS gene promoters, which occurred in concert with mRNA expression. Inhibition of G9a/GLP in the EC, but not in the hippocampus, enhanced contextual fear conditioning relative to control animals. The inhibition of G9a/GLP in the EC induced several histone modifications that include not only methylation but also acetylation. Surprisingly, we found that down-regulation of G9a/GLP activity in the EC enhanced H3K9me2 in area CA1, resulting in transcriptional silencing of the non-memory permissive gene COMT in the hippocampus. In addition, synaptic plasticity studies at two distinct EC-CA1 cellular pathways revealed that G9a/GLP activity is critical for hippocampus-dependent long-term potentiation initiated in the EC via the perforant pathway, but not the temporoammonic pathway. Together, these data demonstrate that G9a/GLP differentially regulates gene transcription in the hippocampus and the EC during memory consolidation. Furthermore, these findings support the possibility of role for G9a/GLP in the regulation of cellular and molecular cross-talk between these two brain regions during LTM formation.

We report that acutely increasing O-GlcNAcylation in Sprague Dawley rat hippocampal slices induces an NMDA receptor and protein kinase C-independent long-term depression (LTD) at hippocampal CA3-CA1 synapses (O-GcNAc LTD). This LTD requires AMPAR GluA2 subunits, which we demonstrate are O-GlcNAcylated. Increasing O-GlcNAcylation interferes with long-term potentiation, and in hippocampal behavioral assays, it prevents novel object recognition and placement without affecting contextual fear conditioning. Our findings provide evidence that O-GlcNAcylation dynamically modulates hippocampal synaptic function and learning and memory, and suggest that altered O-GlcNAc levels could underlie cognitive dysfunction in neurological diseases.

Center ceived little attention.We have examined synaptic plasticity of stratum radi-Durham, North Carolina 27710 atum (s. radiatum) interneurons in the hippocampal CA1 region, which is the site of the most intensively studied form of long-term potentiation (LTP). Excitatory affer-Summary ents from the CA3 region make en passant synapses on multiple pyramidal cells that exhibit synapse-specific Individual GABAergic interneurons in hippocampus (homosynaptic) LTP. The same CA3 afferents excite not can powerfully inhibit more than a thousand excitatory only pyramidal cells but also their interneuron neighbors pyramidal neurons. Therefore, control of interneuron in s. radiatum, which probably mediate the powerful excitability provides control over hippocampal net-"feedforward" inhibition present in CA1 pyramidal cells works. We have identified a novel mechanism in hip-(Fox and Ranck, 1981; Alger and Nicoll, 1982; Buzsaki pocampus that weakens excitatory synapses onto and Eidelberg, 1982; Buzsaki, 1984; Ashwood et al., GABAergic interneurons. Following stimulation that 1984; Frotscher et al., 1984; Schwartzkroin and Kunkel, elicits long-term potentiation at neighboring synapses 1985). onto excitatory cells, excitatory synapses onto inhibi-Using visualized whole-cell patch-clamp recordings, tory interneurons undergo a long-term synaptic dewe find that the same stimulation that elicits LTP in pression (interneuron LTD; iLTD). Unlike most other pyramidal cells markedly depresses excitatory synforms of hippocampal synaptic plasticity, iLTD is not apses onto CA1 interneurons in s. radiatum. We further synapse specific: stimulation of an afferent pathway report that, unlike most other forms of synaptic plasticity triggers depression not only of activated synapses but in hippocampus, the long-lasting depression in inalso of inactive excitatory synapses onto the same terneurons weakens not just active synapses but multiinterneuron. These results suggest that high frequency ple excitatory synapses onto the same interneuron. An afferent activity increases hippocampal excitability obvious consequence of this depression will be a potent through a dual mechanism, simultaneously potentiatenhancement of the excitability of hundreds of pyramiing synapses onto excitatory neurons and depressing dal cells normally innervated by each interneuron. synapses onto inhibitory neurons. Results

Background Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of Fragile X Syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes. Methods We tested if specific GSK3 inhibitors improve deficits in N-methyl-D-aspartate receptor (NMDAR)-dependent long term potentiation (LTP) at medial perforant path synapses onto dentate granule cells (MPP-DGC) and dentate gyrus-dependent cognitive behavioral tasks. Results GSK3 inhibitors completely rescued deficits in LTP at MPP-DGC synapses in FX mice. Furthermore, synaptosomes from the dentate gyrus of FX mice displayed decreased inhibitory serine-phosphorylation of GSK3β compared with wild-type littermates. The potential therapeutic utility of GSK3 inhibitors was further tested on dentate gyrus-dependent congnitive behaviors. In vivo administration of GSK3 inhibitors completely reversed impairments in several cognitive tasks in FX mice, including novel object detection, coordinate and categorical spatial processing, and temporal ordering for visual objects. Conclusions These findings establish that synaptic plasticity and cognitive deficits in FX mice can be improved by intervention with inhibitors of GSK3, which may prove therapeutically beneficial in FXS.

Low-dose ketamine, an open-channel -methyl d-aspartate receptor (NMDAR) antagonist, mediates rapid antidepressant effects in humans that are mimicked in preclinical rodent models. Disinhibition of pyramidal cells via decreased output of fast-spiking GABAergic interneurons has been proposed as a key mechanism that triggers the antidepressant response. Unfortunately, to date, disinhibition has not been directly demonstrated. Furthermore, whether disinhibition is a common mechanism shared among other antagonists with rapid antidepressant properties in humans has not been investigated. Using in vitro electrophysiology in acute slices of dorsal hippocampus from adult male Sprague-Dawley rats, we examined the immediate effects of a clinically relevant concentration of ketamine to directly test the disinhibition hypothesis. As a mechanistic comparison, we also tested the effects of the glycine site NMDAR partial agonist/antagonist GLYX-13 (rapastinel), the GluN2B subunit-selective NMDAR antagonist Ro 25-6981, and the muscarinic acetylcholine receptor (mAChR) antagonist scopolamine. Low-dose ketamine, GLYX-13, and scopolamine reduced inhibitory input onto pyramidal cells and increased synaptically driven pyramidal cell excitability measured at the single-cell and population levels. Conversely, Ro 25-6981 increased the strength of inhibitory transmission and did not change pyramidal cell excitability. These results show a decrease in the inhibition/excitation balance that supports disinhibition as a common mechanism shared among those antagonists with rapid antidepressant properties. These data suggest that pyramidal cell disinhibition downstream of NMDAR antagonism could serve as a possible biomarker for the efficacy of rapid antidepressant therapy.