The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.

The Association of Hippocampal Long-Term Potentiation-Induced Gene Expression with Genetic Risk for Psychosis.

Genomic studies focusing on the contribution of common and rare genetic variants of schizophrenia and bipolar disorder support the view that substantial risk is conferred through molecular pathways involved in synaptic plasticity in the neurons of cortical and subcortical brain regions, including the hippocampus. Synaptic long-term potentiation (LTP) is central to associative learning and memory and depends on a pattern of gene expression in response to neuronal stimulation. Genes related to the induction of LTP have been associated with psychiatric genetic risk, but the specific cell types and timepoints responsible for the association are unknown. Using published genomic and transcriptomic datasets, we studied the relationship between temporally defined gene expression in hippocampal pyramidal neurons following LTP and enrichment for common genetic risk for schizophrenia and bipolar disorder, and for copy number variants (CNVs) and de novo coding variants associated with schizophrenia. We observed that upregulated genes in hippocampal pyramidal neurons at 60 and 120 min following LTP induction were enriched for common variant association with schizophrenia and bipolar disorder subtype I. At 60 min, LTP-induced genes were enriched in duplications from patients with schizophrenia, but this association was not specific to pyramidal neurons, perhaps reflecting the combined effects of CNVs in excitatory and inhibitory neuron subtypes. Gene expression following LTP was not related to enrichment for de novo coding variants from schizophrenia cases. Our findings refine our understanding of the role LTP-related gene sets play in conferring risk to conditions causing psychosis and provide a focus for future studies looking to dissect the molecular mechanisms associated with this risk.

GPER1 deficiency causes sex-specific dysregulation of hippocampal plasticity and cognitive function.

Estrogens regulate synaptic properties and influence hippocampus-related learning and memory via estrogen receptors, which include the G-protein-coupled estrogen receptor 1 (GPER1). Studying mice, in which the GPER1 gene is dysfunctional (GPER1-KO), we here provide evidence for sex-specific roles of GPER1 in these processes. GPER1-KO males showed reduced anxiety in the elevated plus maze, whereas the fear response ('freezing') was specifically increased in GPER1-KO females in a contextual fear conditioning paradigm. In the Morris water maze, spatial learning and memory consolidation was impaired by GPER1 deficiency in both sexes. Notably, in the females, spatial learning deficits and the fear response were more pronounced if mice were in a stage of the estrous cycle, in which E2 serum levels are high (proestrus) or rising (diestrus). On the physiological level, excitability at Schaffer collateral synapses in CA1 increased in GPER1-deficient males and in proestrus/diestrus ('E2 high') females, concordant with an increased hippocampal expression of the AMPA-receptor subunit GluA1 in GPER1-KO males and females as compared to wildtype males. Further changes included an augmented early long-term potentiation (E-LTP) maintenance specifically in GPER1-KO females and an increased hippocampal expression of spinophilin in metestrus/estrus ('E2 low') GPER1-KO females. Our findings suggest modulatory and sex-specific functions of GPER1 in the hippocampal network, which reduce rather than increase neuronal excitability. Dysregulation of these functions may underlie sex-specific cognitive deficits or mood disorders.

Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits.

ADNP syndrome, involving the ADNP transcription factor of the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). Although Adnp-haploinsufficient (Adnp-HT) mice display various phenotypic deficits, whether these mice display abnormal synaptic functions remain poorly understood. Here, we report synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIα hyperactivity in Adnp-HT mice. These mice show impaired and inflexible contextual learning and memory, additional to social deficits, long after the juvenile-stage decrease of ADNP protein levels to ~10% of the newborn level. The adult Adnp-HT hippocampus shows hyperphosphorylated CaMKIIα and its substrates, including SynGAP1, and excessive long-term potentiation that is normalized by CaMKIIα inhibition. Therefore, Adnp haploinsufficiency in mice leads to cognitive inflexibility involving CaMKIIα hyperphosphorylation and excessive LTP in adults long after its marked expressional decrease in juveniles.

Astrocytic A2A receptors silencing negatively impacts hippocampal synaptic plasticity and memory of adult mice.

Astrocytes are wired to bidirectionally communicate with neurons namely with synapses, thus shaping synaptic plasticity, which in the hippocampus is considered to underlie learning and memory. Adenosine A2A receptors (A2A R) are a potential candidate to modulate this bidirectional communication, since A2A R regulate synaptic plasticity and memory and also control key astrocytic functions. Nonetheless, little is known about the role of astrocytic A2A R in synaptic plasticity and hippocampal-dependent memory. Here, we investigated the impact of genetic silencing astrocytic A2A R on hippocampal synaptic plasticity and memory of adult mice. The genetic A2A R silencing in astrocytes was accomplished by a bilateral injection into the CA1 hippocampal area of a viral construct (AAV5-GFAP-GFP-Cre) that inactivate A2A R expression in astrocytes of male adult mice carrying "floxed" A2A R gene, as confirmed by A2A R binding assays. Astrocytic A2A R silencing alters astrocytic morphology, typified by an increment of astrocytic arbor complexity, and led to deficits in spatial reference memory and compromised hippocampal synaptic plasticity, typified by a reduction of LTP magnitude and a shift of synaptic long-term depression (LTD) toward LTP. These data indicate that astrocytic A2A R control astrocytic morphology and influence hippocampal synaptic plasticity and memory of adult mice in a manner different from neuronal A2A R.

Fmr1-KO mice failure to detect object novelty associates with a post-test decrease of structural and synaptic plasticity upstream of the hippocampus.

Mice with deletion of the FMR1 gene show episodic memory impairments and exhibit dendritic spines and synaptic plasticity defects prevalently identified in non-training conditions. Based on evidence that synaptic changes associated with normal or abnormal memory emerge when mice are cognitively challenged, here we examine whether, and how, fragile entorhinal and hippocampal synapses are remodeled when mice succeed or fail to learn. We trained Fmr1 knockout (KO) and wild-type C57BL/6J (WT) mice in the novel object recognition (NOR) paradigm with 1 h or 24 h training-to-test intervals and then assessed whether varying the time between the presentation of similar and different objects modulates NOR performance and plasticity along the entorhinal cortex-hippocampus axis. At the 1 h-interval, KO mice failed to discriminate the novel object, showed a collapse of spines in the lateral entorhinal cortex (LEC), and of long-term potentiation (LTP) in the lateral perforant path (LPP), but a normal increase in hippocampal spines. At the 24 h, they exhibited intact NOR performance, typical LEC and hippocampal spines, and exaggerated LPP-LTP. Our findings reveal that the inability of mice to detect object novelty primarily stands in their impediment to elaborate, and convey to the hippocampus, sensory/perceptive object representations.

Long-term potentiation and depression regulatory microRNAs were highlighted in Bisphenol A induced learning and memory impairment by microRNA sequencing and bioinformatics analysis.

The mechanisms of Bisphenol A (BPA) induced learning and memory impairment have still not been fully elucidated. MicroRNAs (miRNAs) are endogenous non-coding small RNA molecules involved in the process of toxicant-induced neurotoxicity. To investigate the role of miRNAs in BPA-induced learning and memory impairment, we analyzed the impacts of BPA on miRNA expression profile by high-throughput sequencing in mice hippocampus. Results showed that mice treated with BPA displayed impairments of spatial learning and memory and changes in the expression of miRNAs in the hippocampus. Seventeen miRNAs were significantly differentially expressed after BPA exposure, of these, 13 and 4 miRNAs were up- and downregulated, respectively. Bioinformatic analysis of Gene Ontology (GO) and pathway suggests that BPA exposure significantly triggered transcriptional changes of miRNAs associated with learning and memory; the top five affected pathways involved in impairment of learning and memory are: 1) Long-term depression (LTD); 2) Thyroid hormone synthesis; 3) GnRH signaling pathway; 4) Long-term potentiation (LTP); 5) Serotonergic synapse. Eight BPA-responsive differentially expressed miRNAs regulating LTP and LTD were further screened to validate the miRNA sequencing data using Real-Time PCR. The deregulation expression levels of proteins of five target genes (CaMKII, MEK1/2, IP3R, AMPAR1 and PLCß4) were investigated via western blot, for further verifying the results of gene target analysis. Our results showed that LTP and LTD related miRNAs and their targets could contribute to BPA-induced impairment of learning and memory. This study provides valuable information for novel miRNA biomarkers to detect changes in impairment of learning and memory induced by BPA exposure.

Branch point strength controls species-specific CAMK2B alternative splicing and regulates LTP.

Regulation and functionality of species-specific alternative splicing has remained enigmatic to the present date. Calcium/calmodulin-dependent protein kinase IIß (CaMKIIß) is expressed in several splice variants and plays a key role in learning and memory. Here, we identify and characterize several primate-specific CAMK2B splice isoforms, which show altered kinetic properties and changes in substrate specificity. Furthermore, we demonstrate that primate-specific CAMK2B alternative splicing is achieved through branch point weakening during evolution. We show that reducing branch point and splice site strengths during evolution globally renders constitutive exons alternative, thus providing novel mechanistic insight into cis-directed species-specific alternative splicing regulation. Using CRISPR/Cas9, we introduce a weaker, human branch point sequence into the mouse genome, resulting in strongly altered Camk2b splicing in the brains of mutant mice. We observe a strong impairment of long-term potentiation in CA3-CA1 synapses of mutant mice, thus connecting branch point-controlled CAMK2B alternative splicing with a fundamental function in learning and memory.

Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity.

Copy number variants indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Here, hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/- rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Dlg2+/- rats had reduced supra-linear dendritic integration of synaptic inputs resulting in impaired associative long-term potentiation. This impairment was not caused by a change in synaptic input since NMDA receptor-mediated synaptic currents were, conversely, increased and AMPA receptor-mediated currents were unaffected. Instead, the impairment in associative long-term potentiation resulted from an increase in potassium channel function leading to a decrease in input resistance, which reduced supra-linear dendritic integration. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28-1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long-term potentiation impairment in the Dlg2+/- rats. These findings demonstrate a biological phenotype that can be reversed by compound classes used clinically, such as muscarinic M1 receptor agonists, and is therefore a potential target for therapeutic intervention.

Enhanced long-term potentiation and impaired learning in mice lacking alternative exon 33 of CaV1.2 calcium channel.

The CACNA1C (calcium voltage-gated channel subunit alpha 1 C) gene that encodes the CaV1.2 channel is a prominent risk gene for neuropsychiatric and neurodegenerative disorders with cognitive and social impairments like schizophrenia, bipolar disorders, depression and autistic spectrum disorders (ASD). We have shown previously that mice with exon 33 deleted from CaV1.2 channel (CaV1.2-exon 33-/-) displayed increased CaV1.2 current density and single channel open probability in cardiomyocytes, and were prone to develop arrhythmia. As Ca2+ entry through CaV1.2 channels activates gene transcription in response to synaptic activity, we were intrigued to explore the possible role of Cav1.2Δ33 channels in synaptic plasticity and behaviour. Homozygous deletion of alternative exon 33 resulted in enhanced long-term potentiation (LTP), and lack of long- term depression (LTD), which did not correlate with enhanced learning. Exon 33 deletion also led to a decrease in social dominance, sociability and social novelty. Our findings shed light on the effect of gain-of-function of CaV1.2Δ33 signalling on synaptic plasticity and behaviour and provides evidence for a link between CaV1.2 and distinct cognitive and social behaviours associated with phenotypic features of psychiatric disorders like schizophrenia, bipolar disorder and ASD.

Impaired hippocampal NMDAR-LTP in a transgenic model of NSUN2-deficiency.

Biallelic loss-of-function NSUN2 mutations have recently been associated with cases of Autism Spectrum Condition (ASC), and NSun2-deficiency was also previously shown to cause a severe autosomal recessive intellectually disability disorder syndrome in which patients can sometimes display autistic behaviour. It has been demonstrated that NSUN2 can control protein synthesis rates via direct regulation of RNA methylation, and it is therefore of interest that other studies have suggested protein synthesis-dependent synaptic plasticity dysregulation as a mechanism for learning difficulties in various other autism-expressing conditions and disorders. Here we investigated NMDAR-LTP in a murine transgenic model harbouring loss-of-function mutation in the NSun2 gene and find an impairment of a protein synthesis-dependent form of this synaptic plasticity pathway. Our findings support the idea that NMDAR-LTP mis-regulation may represent a previously underappreciated mechanism associated with autism phenotypes.

[PHF10, a Subunit of the PBAF Chromatin Remodeling Complex, Changes Its Localization and Interacts with c-FOS during the Initiation of Long-Term Potentiation in Neuronal Culture].

The PBAF chromatin remodeling complex interacts with many transcriptional activators and is recruited to target chromatin regions. PBAF plays an important role in maintaining and modifying the chromatin structure in mammalian cells. A subunit of the PBAF complex, the PHF10 transcription factor, is required for proliferation of neuronal precursors in the early stages of mouse brain development and gene expression in differentiated neurons. We showed that PHF10 interacts with the protein product of the early response gene c-FOS, the c-FOS transcriptional activator, which is expressed in response to the induction of long-term potentiation (LTP). LTP induction triggers the transcription of genes and the synthesis of proteins that provide changes that lead to the establishment of long-term contacts between neurons. We showed that in cells in differentiated neuronal culture, after the induction of LTP, expression of c-FOS, which is initially localized in the cytoplasm and then moves to the nucleus, begins. PHF10 is expressed in neuronal cells prior to LTP induction and has nuclear localization. However, 1 h after LTP induction, PHF10 is detected in the cytoplasm together with c-FOS, and then moves into the nucleus with it. Importantly, this behavior of PHF10 in response to KC1 stimulation is specific for neuronal cultures. It is assumed that during LTP, PHF10 together with c-FOS participates in the activation of secondary response genes that regulate the maintenance of plastic modifications and homeostasis of neuronal synapses. The PHF10 export from the nucleus and its rapid return together with c-FOS to the nucleus is possibly necessary for the rapid modulation of expression of target secondary response genes during LTP.

Astrocytic microdomains from mouse cortex gain molecular control over long-term information storage and memory retention.

Memory consolidation requires astrocytic microdomains for protein recycling; but whether this lays a mechanistic foundation for long-term information storage remains enigmatic. Here we demonstrate that persistent synaptic strengthening invited astrocytic microdomains to convert initially internalized (pro)-brain-derived neurotrophic factor (proBDNF) into active prodomain (BDNFpro) and mature BDNF (mBDNF) for synaptic re-use. While mBDNF activates TrkB, we uncovered a previously unsuspected function for the cleaved BDNFpro, which increases TrkB/SorCS2 receptor complex at post-synaptic sites. Astrocytic BDNFpro release reinforced TrkB phosphorylation to sustain long-term synaptic potentiation and to retain memory in the novel object recognition behavioral test. Thus, the switch from one inactive state to a multi-functional one of the proBDNF provides post-synaptic changes that survive the initial activation. This molecular asset confines local information storage in astrocytic microdomains to selectively support memory circuits.

A novel role for the ADHD risk gene latrophilin-3 in learning and memory in Lphn3 knockout rats.

Latrophilins (LPHNs) are adhesion G protein-coupled receptors with three isoforms but only LPHN3 is brain specific (caudate, prefrontal cortex, dentate, amygdala, and cerebellum). Variants of LPHN3 are associated with ADHD. Null mutations of Lphn3 in rat, mouse, zebrafish, and Drosophila result in hyperactivity, but its role in learning and memory (L&M) is largely unknown. Using our Lphn3 knockout (KO) rats we examined the cognitive abilities, long-term potentiation (LTP) in CA1, NMDA receptor expression, and neurohistology from heterozygous breeding pairs. KO rats were impaired in egocentric L&M in the Cincinnati water maze, spatial L&M and cognitive flexibility in the Morris water maze (MWM), with no effects on conditioned freezing, novel object recognition, or temporal order recognition. KO-associated locomotor hyperactivity had no effect on swim speed. KO rats had reduced early-LTP but not late-LTP and had reduced hippocampal NMDA-NR1 expression. In a second experiment, KO rats responded to a light prepulse prior to an acoustic startle pulse, reflecting visual signal detection. In a third experiment, KO rats given extra MWM pretraining and hidden platform overtraining showed no evidence of reaching WT rats' levels of learning. Nissl histology revealed no structural abnormalities in KO rats. LPHN3 has a selective effect on egocentric and allocentric L&M without effects on conditioned freezing or recognition memory.

AMPA receptor trafficking and LTP: Carboxy-termini, amino-termini and TARPs.

AMPA receptors (AMPARs) are fundamental elements in excitatory synaptic transmission and synaptic plasticity in the CNS. Long term potentiation (LTP), a form of synaptic plasticity which contributes to learning and memory formation, relies on the accumulation of AMPARs at the postsynapse. This phenomenon requires the coordinated recruitment of different elements in the AMPAR complex. Based on recent research reviewed herein, we propose an updated AMPAR trafficking and LTP model which incorporates both extracellular as well as intracellular mechanisms. This article is part of the special Issue on 'Glutamate Receptors - AMPA receptors'.

Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome.

Perineuronal nets (PNNs), a specialized form of extracellular matrix, are abnormal in the brains of people with Rett syndrome (RTT). We previously reported that PNNs function to restrict synaptic plasticity in hippocampal area CA2, which is unusually resistant to long-term potentiation (LTP) and has been linked to social learning in mice. Here we report that PNNs appear elevated in area CA2 of the hippocampus of an individual with RTT and that PNNs develop precociously and remain elevated in area CA2 of a mouse model of RTT (Mecp2-null). Further, we provide evidence that LTP could be induced at CA2 synapses prior to PNN maturation (postnatal day 8-11) in wild-type mice and that this window of plasticity was prematurely restricted at CA2 synapses in Mecp2-null mice. Degrading PNNs in Mecp2-null hippocampus was sufficient to rescue the premature disruption of CA2 plasticity. We identified several molecular targets that were altered in the developing Mecp2-null hippocampus that may explain aberrant PNNs and CA2 plasticity, and we discovered that CA2 PNNs are negatively regulated by neuronal activity. Collectively, our findings demonstrate that CA2 PNN development is regulated by Mecp2 and identify a window of hippocampal plasticity that is disrupted in a mouse model of RTT.

Increased excitability of hippocampal neurons in mature synaptopodin-knockout mice.

Synaptopodin (SP) is localized within the spine apparatus, an enigmatic structure located in the neck of spines of central excitatory neurons. It serves as a link between the spine head, where the synapse is located, and the endoplasmic reticulum (ER) in the parent dendrite. SP is also located in the axon initial segment, in association with the cisternal organelle, another structure related to the endoplasmic reticulum. Extensive research using SP knockout (SPKO) mice suggest that SP has a pivotal role in structural and functional plasticity. Consequently, young adult SPKO mice were shown to be deficient in cognitive functions, and in ability to undergo long-term potentiation of reactivity to afferent stimulation. However, although SP expresses differently during maturation, its role in synaptic and intrinsic neuronal mechanisms in adult SPKO mice is still unclear. To address this knowledge gap we analyzed hippocampus bulk mRNA in SPKO mice, and we recorded the activity of CA1 neurons in the mouse hippocampus slice, with both extracellular and patch recording methods. Electrophysiologically, SPKO cells in CA1 region of the dorsal hippocampus were more excitable than wild type (wt) ones. In addition, exposure of mice to a complex environment caused a higher proportion of arc-expressing cells in SPKO than in wt mice hippocampus. These experiments indicate that higher excitability and higher expression of arc staining may reflect SP deficiency in the hippocampus of adult SPKO mice.

Serine/Threonine Phosphatases in LTP: Two B or Not to Be the Protein Synthesis Blocker-Induced Impairment of Early Phase.

Dephosphorylation of target proteins at serine/threonine residues is one of the most crucial mechanisms regulating their activity and, consequently, the cellular functions. The role of phosphatases in synaptic plasticity, especially in long-term depression or depotentiation, has been reported. We studied serine/threonine phosphatase activity during the protein synthesis blocker (PSB)-induced impairment of long-term potentiation (LTP). Established protein phosphatase 2B (PP2B, calcineurin) inhibitor cyclosporin A prevented the LTP early phase (E-LTP) decline produced by pretreatment of hippocampal slices with cycloheximide or anisomycin. For the first time, we directly measured serine/threonine phosphatase activity during E-LTP, and its significant increase in PSB-treated slices was demonstrated. Nitric oxide (NO) donor SNAP also heightened phosphatase activity in the same manner as PSB, and simultaneous application of anisomycin + SNAP had no synergistic effect. Direct measurement of the NO production in hippocampal slices by the NO-specific fluorescent probe DAF-FM revealed that PSBs strongly stimulate the NO concentration in all studied brain areas: CA1, CA3, and dentate gyrus (DG). Cyclosporin A fully abolished the PSB-induced NO production in the hippocampus, suggesting a close relationship between nNOS and PP2B activity. Surprisingly, cyclosporin A alone impaired short-term plasticity in CA1 by decreasing paired-pulse facilitation, which suggests bi-directionality of the influences of PP2B in the hippocampus. In conclusion, we proposed a minimal model of signaling events that occur during LTP induction in normal conditions and the PSB-treated slices.

Characterization of the Functional Cross-Talk between Surface GABAA and Dopamine D5 Receptors.

The γ-aminobutyric acid type A receptor (GABAAR) plays a major role in fast inhibitory synaptic transmission and is highly regulated by the neuromodulator dopamine. In this aspect, most of the attention has been focused on the classical intracellular signaling cascades following dopamine G-protein-coupled receptor activation. Interestingly, the GABAAR and dopamine D5 receptor (D5R) have been shown to physically interact in the hippocampus, but whether a functional cross-talk occurs is still debated. In the present study, we use a combination of imaging and single nanoparticle tracking in live hippocampal neurons to provide evidence that GABAARs and D5Rs form dynamic surface clusters. Disrupting the GABAAR-D5R interaction with a competing peptide leads to an increase in the diffusion coefficient and the explored area of both receptors, and a drop in immobile synaptic GABAARs. By means of patch-clamp recordings, we show that this fast lateral redistribution of surface GABAARs correlates with a robust depression in the evoked GABAergic currents. Strikingly, it also shifts in time the expression of long-term potentiation at glutamatergic synapses. Together, our data both set the plasma membrane as the primary stage of a functional interplay between GABAAR and D5R, and uncover a non-canonical role in regulating synaptic transmission.

Forebrain GluN2A overexpression impairs fear extinction and NMDAR-dependent long-term depression in the lateral amygdala.

N-methyl-d-aspartic acid receptor (NMDAR)-dependent synaptic plasticity at the thalamus-lateral amygdala (T-LA) synapses is related to acquisition and extinction of auditory fear memory. However, the roles of the NMDAR GluN2A subunit in acquisition and extinction of auditory fear memory as well as synaptic plasticity at T-LA synapses remain unclear. Here, using electrophysiologic, molecular biological techniques and behavioral methods, we found that the forebrain specific GluN2A overexpression transgenic (TG) mice exhibited normal acquisition but impaired extinction of auditory fear memory. In addition, in vitro electrophysiological data showed normal basal synaptic transmission and NMDAR-dependent long-term potentiation (LTP) at T-LA synapses, but deficit in NMDAR-dependent long-term depression (LTD) at T-LA synapses in GluN2A TG mice. Consistent with the reduced NMDAR-dependent LTD, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization was also weakened during NMDAR-dependent LTD in GluN2A TG mice. Taken together, our findings for the first time indicate that GluN2A overexpression impairs extinction of auditory fear memory and NMDAR-dependent LTD at T-LA synapses, which further confirms the close relationship between NMDAR-dependent LTD and fear extinction.