NMDA Receptor-dependent Synaptic Plasticity Research Articles

HDAC2 in Primary Sensory Neurons Constitutively Restrains Chronic Pain by Repressing α2δ-1 Expression and Associated NMDA Receptor Activity.

α2δ-1 (encoded by the Cacna2d1 gene) is a newly discovered NMDA receptor-interacting protein and is the therapeutic target of gabapentinoids (e.g., gabapentin and pregabalin) frequently used for treating patients with neuropathic pain. Nerve injury causes sustained α2δ-1 upregulation in the dorsal root ganglion (DRG), which promotes NMDA receptor synaptic trafficking and activation in the spinal dorsal horn, a hallmark of chronic neuropathic pain. However, little is known about how nerve injury initiates and maintains the high expression level of α2δ-1 to sustain chronic pain. Here, we show that nerve injury caused histone hyperacetylation and diminished enrichment of histone deacetylase-2 (HDAC2), but not HDAC3, at the Cacna2d1 promoter in the DRG. Strikingly, Hdac2 knockdown or conditional knockout in DRG neurons in male and female mice consistently induced long-lasting mechanical pain hypersensitivity, which was readily reversed by blocking NMDA receptors, inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1-NMDA receptor interaction at the spinal cord level. Hdac2 deletion in DRG neurons increased histone acetylation levels at the Cacna2d1 promoter, upregulated α2δ-1 in the DRG, and potentiated α2δ-1-dependent NMDA receptor activity at primary afferent central terminals in the spinal dorsal horn. Correspondingly, Hdac2 knockdown-induced pain hypersensitivity was blunted in Cacna2d1 knockout mice. Thus, our findings reveal that HDAC2 functions as a pivotal transcriptional repressor of neuropathic pain via constitutively suppressing α2δ-1 expression and ensuing presynaptic NMDA receptor activity in the spinal cord. HDAC2 enrichment levels at the Cacna2d1 promoter in DRG neurons constitute a unique epigenetic mechanism that governs acute-to-chronic pain transition.SIGNIFICANCE STATEMENT Excess α2δ-1 proteins produced after nerve injury directly interact with glutamate NMDA receptors to potentiate synaptic NMDA receptor activity in the spinal cord, a prominent mechanism of nerve pain. Because α2δ-1 upregulation after nerve injury is long lasting, gabapentinoids relieve pain symptoms only temporarily. Our study demonstrates for the first time the unexpected role of intrinsic HDAC2 activity at the α2δ-1 gene promoter in limiting α2δ-1 gene transcription, NMDA receptor-dependent synaptic plasticity, and chronic pain development after nerve injury. These findings challenge the prevailing view about the role of general HDAC activity in promoting chronic pain. Restoring the repressive HDAC2 function and/or reducing histone acetylation at the α2δ-1 gene promoter in primary sensory neurons could lead to long-lasting relief of nerve pain.

Intermittent Hypoxia causes targeted disruption to NMDA receptor dependent synaptic plasticity in area CA1 of the hippocampus

Changed NMDA receptor (NMDAr) physiology is implicated with cognitive deficit resulting from conditions ranging from normal aging to neurological disease. Using intermittent hypoxia (IH) to experimentally model untreated sleep apnea, a clinical condition whose comorbidities include neurocognitive impairment, we recently demonstrated that IH causes a pro-oxidant condition that contributes to deficits in spatial memory and in NMDAr-dependent long-term potentiation (LTP). However, the impact of IH on additional forms of synaptic plasticity remains ill-defined. Here we show that IH prevents the induction of NMDAr-dependent LTP and long-term depression (LTD) in hippocampal brain slices from mice exposed to ten days of IH (IH10) yet spares NMDAr-independent forms of synaptic plasticity. Deficits in synaptic plasticity were accompanied by a reduction in hippocampal GluN1 expression. Acute manipulation of redox state using the reducing agent, Dithiothreitol (DTT) stimulated the NMDAr-dependent fEPSP following IH10. However, acute use of either DTT or MnTMPyP did not restore NMDAr-dependent synaptic plasticity after IH10 or prevent the IH-dependent reduction in GluN1, the obligatory subunit of the NMDAr. In contrast, MnTMPyP during IH10 (10-MnTMPyP), prevented the suppressive effects of IH on both NMDAr-dependent synaptic plasticity and GluN1 expression. These findings indicate that while the IH-dependent pro-oxidant state causes reversible oxidative neuromodulation of NMDAr activity, acute manipulation of redox state is ineffective in rescuing two key effects of IH related to the NMDAr within the hippocampus. These IH-dependent changes associated with the NMDAr may be a primary avenue by which IH enhances the vulnerability to impaired learning and memory when sleep apnea is left untreated in normal aging and in disease.

Plasticity in Prefrontal Cortex Induced by Coordinated Synaptic Transmission Arising from Reuniens/Rhomboid Nuclei and Hippocampus.

The nucleus reuniens and rhomboid nuclei of the thalamus (ReRh) are reciprocally connected to a range of higher order cortices including hippocampus (HPC) and medial prefrontal cortex (mPFC). The physiological function of ReRh is well predicted by requirement for interactions between mPFC and HPC, including associative recognition memory, spatial navigation, and working memory. Although anatomical and electrophysiological evidence suggests ReRh makes excitatory synapses in mPFC there is little data on the physiological properties of these projections, or whether ReRh and HPC target overlapping cell populations and, if so, how they interact. We demonstrate in ex vivo mPFC slices that ReRh and HPC afferent inputs converge onto more than two-thirds of layer 5 pyramidal neurons, show that ReRh, but not HPC, undergoes marked short-term plasticity during theta frequency transmission, and that HPC, but not ReRh, afferents are subject to neuromodulation by acetylcholine acting via muscarinic receptor M2. Finally, we demonstrate that pairing HPC followed by ReRh (but not pairing ReRh followed by HPC) at theta frequency induces associative, NMDA receptor dependent synaptic plasticity in both inputs to mPFC. These data provide vital physiological phenotypes of the synapses of this circuit and provide a novel mechanism for HPC–ReRh–mPFC encoding.

Deletion of Glycogen Synthase Kinase-3β in D2 Receptor–Positive Neurons Ameliorates Cognitive Impairment via NMDA Receptor–Dependent Synaptic Plasticity

BackgroundCortical dopaminergic systems are critically involved in prefrontal cortex (PFC) functions, especially in working memory and neurodevelopmental disorders such as schizophrenia. GSK-3β (glycogen synthase kinase-3β) is highly associated with cAMP (cyclic adenosine monophosphate)–independent dopamine D2 receptor (D2R)-mediated signaling to affect dopamine-dependent behaviors. However, the mechanisms underlying the GSK-3β modulation of cognitive function via D2Rs remains unclear. MethodsThis study explored how conditional cell-type–specific ablation of GSK-3β in D2R+ neurons (D2R-GSK-3β−/−) in the brain affects synaptic function in the medial PFC (mPFC). Both male and female (postnatal days 60–90) mice, including 140 D2R, 24 D1R, and 38 DISC1 mice, were used. ResultsThis study found that NMDA receptor (NMDAR) function was significantly increased in layer V pyramidal neurons in mPFC of D2R-GSK-3β−/− mice, along with increased dopamine modulation of NMDAR-mediated current. Consistently, NR2A and NR2B protein levels were elevated in mPFC of D2R-GSK-3β−/− mice. This change was accompanied by a significant increase in enrichment of activator histone mark H3K27ac at the promoters of both Grin2a and Grin2b genes. In addition, altered short- and long-term synaptic plasticity, along with an increased spine density in layer V pyramidal neurons, were detected in D2R-GSK-3β−/− mice. Indeed, D2R-GSK-3β−/− mice also exhibited a resistance of working memory impairment induced by injection of NMDAR antagonist MK-801. Notably, either inhibiting GSK-3β or disrupting the D2R-DISC1 complex was able to reverse the mutant DISC1-induced decrease of NMDAR-mediated currents in the mPFC. ConclusionsThis study demonstrates that GSK-3β modulates cognition via D2R-DISC1 interaction and epigenetic regulation of NMDAR expression and function.

Chronic adolescent exposure to ∆9-tetrahydrocannabinol decreases NMDA current and extrasynaptic plasmalemmal density of NMDA GluN1 subunits in the prelimbic cortex of adult male mice.

Adolescence is a vulnerable period of development when limbic connection of the prefrontal cortex (PFC) involved in emotional processing may be rendered dysfunctional by chronic exposure to delta-9-tetrahydrocannabinol (∆9-THC), the major psychoactive compound in marijuana. Cannabinoid-1 receptors (CB1Rs) largely mediate the central neural effects of ∆9-THC and endocannabinoids that regulate NMDA receptor-dependent synaptic plasticity of glutamatergic synapses in the prelimbic prefrontal cortex (PL-PFC). Thus, chronic occupancy of CB1Rs by ∆9-THC during adolescence may competitively decrease the functional expression and activity of NMDA receptors in the mature PL-PFC. We used a multidisciplinary approach to test this hypothesis in adult C57BL/6J male mice that received vehicle or ∆9-THC in escalating doses (2.5-10 mg/kg/ip) through adolescence (postnatal day 29-43). In comparison with vehicle, the mice receiving ∆9-THC showed a hyperpolarized resting membrane potential, decreased spontaneous firing rate, increased current-induced firing threshold, and decreased depolarizing response to NMDA in deep-layer PL-PFC neurons analyzed by current-clamp recordings. Electron microscopic immunolabeling in the PL-PFC of adult mice that had received Δ9-THC only during adolescence showed a significant (1) decrease in the extrasynaptic plasmalemmal density of obligatory GluN1-NMDA subunits in dendrites of all sizes and (2) a shift from cytoplasmic to plasmalemmal distribution of GluN1 in large dendrites receiving mainly inhibitory-type synapses from CB1R-labeled terminals. From these results and concomitant behavioral studies, we conclude that social dysfunctions resulting from excessive intake of ∆9-THC in the increasingly available marijuana products used by male teens may largely reflect circuit defects in PL-PFC networks communicating through endocannabinoid-regulated NMDA receptors.

The NMDA receptor antagonist MK-801 fails to impair long-term recognition memory in mice when the state-dependency of memory is controlled.

NMDA receptor-dependent synaptic plasticity has been proposed to be important for encoding of memories. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist, MK-801, has been found to impair performance on tests of memory. Interpretation of some of these findings has, however, been complicated by the fact that the drug-state of animals has differed during encoding and tests of memory. Therefore, it is possible that MK-801 may result in state-dependent retrieval or expression of memory rather than actually impairing encoding itself. We tested this hypothesis in mice using tests of object recognition memory with a 24-hour delay between the encoding and test phase. Mice received injections of either vehicle or MK-801 prior to the encoding phase and the test phase. In Experiment 1, a low dose of MK-801 (0.01 mg/kg) impaired performance when the drug-state (vehicle or MK-801) of mice changed between encoding and test, but there was no significant effect of MK-801 on encoding. In Experiment 2, a higher dose of MK-801 (0.1 mg/kg) failed to impair object recognition memory when mice received the drug prior to both encoding and test compared to mice that received vehicle. MK-801 did not affect object exploration, but it did induce locomotor hyperactivity at the higher dose. These results suggest that some previous demonstrations of MK-801 effects may reflect a failure to express or retrieve memory due to the state-dependency of memory rather than impaired encoding of memory.

NMDA receptor-dependent synaptic plasticity of rTMS

NMDA receptor-dependent synaptic plasticity of rTMS

Regulation of Hippocampal Synaptic Function by the Metabolic Hormone, Leptin: Implications for Health and Neurodegenerative Disease.

The role of the endocrine hormone leptin in controlling energy homeostasis in the hypothalamus are well documented. However the CNS targets for leptin are not restricted to the hypothalamus as a high density of leptin receptors are also expressed in several parts of the brain involved in higher cognitive functions including the hippocampus. Numerous studies have identified that in the hippocampus, leptin has cognitive enhancing actions as exogenous application of this hormone facilitates hippocampal-dependent learning and memory, whereas lack or insensitivity to leptin results in significant memory deficits. Leptin also markedly influences some of the main cellular changes that are involved in learning and memory including NMDA-receptor dependent synaptic plasticity and glutamate receptor trafficking. Like other metabolic hormones, there is a significant decline in neuronal sensitivity to leptin during the ageing process. Indeed, the capacity of leptin to modulate the functioning of hippocampal synapses is substantially reduced in aged compared to adult tissue. Clinical studies have also identified an association between circulating leptin levels and the risk of certain neurodegenerative disorders such as Alzheimer’s disease (AD). In view of this, targeting leptin and/or its receptor/signaling mechanisms may be an innovative approach for developing therapies to treat AD. In support of this, accumulating evidence indicates that leptin has cognitive enhancing and neuroprotective actions in various models of AD. Here we assess recent evidence that supports an important regulatory role for leptin at hippocampal CA1 synapses, and we discuss how age-related alterations in this hormonal system influences neurodegenerative disease.

Physiological activation of mGlu5 receptors supports the ion channel function of NMDA receptors in hippocampal LTD induction in vivo

Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor. Endogenous mGlu5 receptor activation necessitated the local application of relatively high doses of either competitive or non-competitive NMDA receptor antagonists to block LTD induction. Moreover, boosting endogenous glutamate activation of mGlu5 receptors with a positive allosteric modulator lowered the threshold for NMDA receptor-dependent LTD induction by weak LFS. The present data provide support in the living animal that NMDA receptor-dependent LTD is boosted by endogenously released glutamate activation of mGlu5 receptors. Given the predominant perisynaptic location of mGlu5 receptors, the present findings emphasize the need to further evaluate the contribution and mechanisms of these receptors in NMDA receptor-dependent synaptic plasticity in the adult hippocampus in vivo.

Prenatal exposure to lambda-cyhalothrin impairs memory in developing rats: Role of NMDA receptor induced post-synaptic signalling in hippocampus

Effect of prenatal exposure to lambda-cyhalothrin (LCT) has been assessed on the integrity of NMDA receptors and associated post-synaptic signalling in hippocampus of developing rats. Decrease in the binding of [3H]-MK 801, known to label NMDA receptors was observed in hippocampus of rats prenatally exposed to LCT (1 and 3mg/kg body weight) on PD22, compared to controls. Consistent with this, decrease in the mRNA and protein expression of NR1 and NR2B subunits of NMDA receptors was evident in rats prenatally exposed to LCT (1 and 3mg/kg body weight) on PD22. There was no change in mRNA and protein expression of NR2A subunit of NMDA receptors. Prenatal exposure to LCT (1 and 3mg/kg body weight) decreased the expression of positive regulators (PSD95, pERK1/2, CaMKIIα & pCREB) and increased the expression of negative regulators (Cdk5 & SynGAP) associated with NMDA receptor dependent synaptic plasticity in hippocampus and impaired learning and memory of rats on PD22. The neurobehavioral changes continued to persist in rats exposed to LCT at high dose (3mg/kg body weight) while exhibited trend of recovery in those exposed at moderate dose (1mg/kg body weight) on PD45, compared to controls. No change in any of the neurobehavioral endpoint was observed in developing rats prenatally exposed to LCT at low dose (0.5mg/kg body weight) on PD22 and PD45. The results exhibit that alterations in NMDA receptors on prenatal exposure to LCT may affect postsynaptic signalling associated with impaired learning and memory in developing rats.

Impaired bidirectional NMDA receptor dependent synaptic plasticity in the dentate gyrus of adult female Fmr1 heterozygous knockout mice

Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmr1 gene resulting in loss of the Fragile-X mental retardation protein (FMRP). This leads to cognitive impairment in both male and female patients, however few studies have focused on the impact of FXS in females. Significant cognitive impairment has been reported in approximately 35% of women who exhibit a heterozygous Fmr1 gene mutation, however to date there is a paucity of information regarding the mechanistic underpinnings of these deficits. We, and others, have recently reported that there is significant impairment in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal dentate gyrus (DG) of male Fmr1 knock out mice. Here we examined if female mice displaying a heterozygous loss of the Fmr1 gene (Fmr1+/‐) would exhibit similar impairments in DG-dependent spatial memory processing and NMDAR hypofunction. We found that Female Fmr1+/‐ mice did not show impaired metabotropic glutamate receptor (mGluR)-LTD in the CA1 region, and could perform well on a temporal ordering task that is thought to involve this brain region. In contrast, female Fmr1+/‐ mice showed impairments in a pattern separation task thought to involve the DG, and also displayed a significant impairment in both NMDAR-dependent LTD and LTP in this region. The LTP impairment could be rescued by administering the NMDAR co-agonist, glycine. Our data suggests that NMDAR hypofunction in the DG may partly contribute to learning and memory impairment in female Fmr1+/‐ mice. Targeting NMDAR-dependent mechanisms may offer hope as a new therapeutic approach for treating female FXS patients with learning and memory impairments.

A spatiotemporal model of spine calcium dynamics in the hippocampus

Ca2+-signalling in dendritic spines is required for NMDA receptor-dependent synaptic plasticity at glutamatergic synapses in the hippocampus [1]. However, it is not clear whether plasticity induction is dependent solely on the global signal, i.e., the spine volume-averaged Ca2+ signal; or whether plasticity induction is also sensitive to Ca2+-channel nanodomain signaling [2]. A working hypothesis of this work is that temporal and spatial variations in postsynaptic intracellular [Ca2+]-fields may be significant factors governing the signalling cascades that lead to either long-term synaptic potentiation or depression. Direct measurement of [Ca2+] distributions in dendritic spines is experimentally difficult but we can investigate this hypothesis using mathematical models of Ca2+ diffusion. We have developed a spatio-temporal model of Ca2+ diffusion in three dimensions. We then study our model using finite element methods. The model allows predictions of intracellular [Ca2+]-field responses to combinations of pre- and post-synaptic spikes with nanometre and millisecond spatio-temporal resolution. Our results so far indicate that Ca2+ signalling is highly spatially non-uniform and that Ca2+ signal differences between induction protocols is dependent on location within the spine. This has implications for the ultimate biological role of the Ca2+ signal given that the relevant receptors in the spine are organised inhomogeneously [3].

Cholinergic, but not NMDA, receptors in the lateral entorhinal cortex mediate acquisition in trace eyeblink conditioning.

Anatomical and electrophysiological studies collectively suggest that the entorhinal cortex consists of several subregions, each of which is involved in the processing of different types of information. Consistent with this idea, we previously reported that the dorsolateral portion of the entorhinal cortex (DLE), but not the caudomedial portion, is necessary for the expression of a memory association between temporally discontiguous stimuli in trace eyeblink conditioning (Morrissey et al. (2012) J Neurosci 32:5356-5361). The present study examined whether memory acquisition depends on the DLE and what types of local neurotransmitter mechanisms are involved in memory acquisition and expression. Male Long-Evans rats experienced trace eyeblink conditioning, in which an auditory conditioned stimulus (CS) was paired with a mildly aversive electric shock to the eyelid (US) with a stimulus-free interval of 500 ms. Immediately before the conditioning, the rats received a microinfusion of neuroreactive substances into the DLE. We found that reversible inactivation of the DLE with GABAA receptor agonist, muscimol impaired memory acquisition. Furthermore, blockade of local muscarinic acetylcholine receptors (mACh) with scopolamine retarded memory acquisition while blockade of local NMDA receptors with APV had no effect. Memory expression was not impaired by either type of receptor blocker. These results suggest that the DLE is necessary for memory acquisition, and that acquisition depends on the integrity of local mACh receptor-dependent firing modulation, but not NMDA receptor-dependent synaptic plasticity.

The palmitoyl acyltransferase DHHC2 regulates recycling endosome exocytosis and synaptic potentiation through palmitoylation of AKAP79/150.

Phosphorylation and dephosphorylation of AMPA-type ionotropic glutamate receptors (AMPARs) by kinases and phosphatases and interactions with scaffold proteins play essential roles in regulating channel biophysical properties and trafficking events that control synaptic strength during NMDA receptor-dependent synaptic plasticity, such as LTP and LTD. We previously demonstrated that palmitoylation of the AMPAR-linked scaffold protein A-kinase anchoring protein (AKAP) 79/150 is required for its targeting to recycling endosomes in dendrites, where it regulates exocytosis from these compartments that is required for LTP-stimulated enlargement of postsynaptic dendritic spines, delivery of AMPARs to the plasma membrane, and maintenance of synaptic potentiation. Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms. In particular, RNAi-mediated knockdown of DHHC2 expression in rat hippocampal neurons disrupted stimulation of exocytosis from recycling endosomes, enlargement of dendritic spines, AKAP recruitment to spines, and potentiation of AMPAR-mediated synaptic currents that occur during LTP. Importantly, expression of a palmitoylation-independent lipidated AKAP mutant in DHHC2-deficient neurons largely restored normal plasticity regulation. Thus, we conclude that DHHC2-AKAP79/150 signaling is an essential regulator of dendritic recycling endosome exocytosis that controls both structural and functional plasticity at excitatory synapses.

Cannabinoid receptors contribute to astroglial Ca²⁺-signalling and control of synaptic plasticity in the neocortex.

Communication between neuronal and glial cells is thought to be very important for many brain functions. Acting via release of gliotransmitters, astrocytes can modulate synaptic strength. The mechanisms underlying ATP release from astrocytes remain uncertain with exocytosis being the most intriguing and debated pathway. We have demonstrated that ATP and d-serine can be released from cortical astrocytes in situ by a SNARE-complex-dependent mechanism. Exocytosis of ATP from astrocytes can activate post-synaptic P2X receptors in the adjacent neurons, causing a downregulation of synaptic and extrasynaptic GABA receptors in cortical pyramidal neurons. We showed that release of gliotransmitters is important for the NMDA receptor-dependent synaptic plasticity in the neocortex. Firstly, induction of long-term potentiation (LTP) by five episodes of theta-burst stimulation (TBS) was impaired in the neocortex of dominant-negative (dn)-SNARE mice. The LTP was rescued in the dn-SNARE mice by application of exogenous non-hydrolysable ATP analogues. Secondly, we observed that weak sub-threshold stimulation (two TBS episodes) became able to induce LTP when astrocytes were additionally activated via CB-1 receptors. This facilitation was dependent on activity of ATP receptors and was abolished in the dn-SNARE mice. Our results strongly support the physiological relevance of glial exocytosis for glia–neuron communications and brain function.

Reduced d-serine levels in the nucleus accumbens of cocaine-treated rats hinder the induction of NMDA receptor-dependent synaptic plasticity

Cocaine seeking behaviour and relapse have been linked to impaired potentiation and depression at excitatory synapses in the nucleus accumbens, but the mechanism underlying this process is poorly understood. We show that, in the rat nucleus accumbens core, D-serine is the endogenous coagonist of N-methyl-D-aspartate receptors, and its presence is essential for N-methyl-D-aspartate receptor-dependent potentiation and depression of synaptic transmission. Nucleus accumbens core slices obtained from cocaine-treated rats after 1 day of abstinence presented significantly reduced D-serine concentrations, increased expression of the D-serine degrading enzyme, D-amino acid oxidase, and downregulated expression of serine racemase, the enzyme responsible for D-serine synthesis. The D-serine deficit was associated with impairment of potentiation and depression of glutamatergic synaptic transmission, which was restored by slice perfusion with exogenous D-serine. Furthermore, in vivo administration of D-serine directly into the nucleus accumbens core blocked behavioural sensitization to cocaine. These results provide evidence for a critical role of D-serine signalling in synaptic plasticity relevant to cocaine addiction.

NMDA receptor-dependent synaptic plasticity in dorsal and intermediate hippocampus exhibits distinct frequency-dependent profiles

The hippocampus may be functionally differentiated along its dorsoventral axis. In contrast to the wealth of data available on synaptic plasticity mechanisms in the dorsal hippocampus, little is known about synaptic plasticity processes in the intermediate hippocampus. Behavioral data suggest that this structure may play a distinct role in learning and memory. Here, we compared amplitudes, frequency-dependency and persistency of long-term potentiation (LTP) and long-term depression (LTD) in the dorsal (DDG) and intermediate dentate gyrus (IDG).In freely moving rats, high-frequency stimulation (HFS) at 200 Hz (10 burst of 15 stimuli) elicited LTP of similar magnitude in both structures that persisted for over 24 h. The intermediate dentate gyrus is more likely to exhibit persistent LTP than its dorsal counterpart, however: HFS at 200 Hz (3 or 1 burst(s)) or 100 Hz elicited short-term potentiation (STP) in DDG, unlike in the IDG, where LTP could be recorded for at least 4 h. Whereas low frequency stimulation (LFS) at 1 Hz elicited long-lasting LTD (>24 h) in the DDG, it had no significant effect on fEPSP profile in the IDG. LFS at 2 Hz elicited short-term depression in DDG and had no effect in IDG. LTP in both IDG and DDG required activation of N-methyl-D-aspartate receptors. Paired-pulse and input–output responses differed in IDG and DDG.Our data suggest that afferent input from the entorhinal cortex generates a different response profile in the dorsal vs. intermediate DG, which may in turn relate to their postulated distinct roles in synaptic information processing and memory formation.This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’.

Locomotor Sensitization to Ethanol Impairs NMDA Receptor-Dependent Synaptic Plasticity in the Nucleus Accumbens and Increases Ethanol Self-Administration

Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percentage of alcohol users become addicted. The specific neural substrates responsible for individual differences in vulnerability to alcohol addiction are not known. In this study, we used rodent models to study behavioral and synaptic correlates related to individual differences in the development of ethanol locomotor sensitization, a form of drug-dependent behavioral plasticity associated with addiction vulnerability. Male Swiss Webster mice were treated daily with saline or 1.8 g/kg ethanol for 21 d. Locomotor activity tests were performed once a week for 15 min immediately after saline or ethanol injections. After at least 11 d of withdrawal, cohorts of saline- or ethanol-treated mice were used to characterize the relationships between locomotor sensitization, ethanol drinking, and glutamatergic synaptic transmission in the nucleus accumbens. Ethanol-treated mice that expressed locomotor sensitization to ethanol drank significantly more ethanol than saline-treated subjects and ethanol-treated animals resilient to this form of behavioral plasticity. Moreover, ethanol-sensitized mice also had reduced accumbal NMDA receptor function and expression, as well as deficits in NMDA receptor-dependent long-term depression in the nucleus accumbens core after a protracted withdrawal. These findings suggest that disruption of accumbal core NMDA receptor-dependent plasticity may represent a synaptic correlate associated with ethanol-induced locomotor sensitization and increased propensity to consume ethanol.

Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity

ObjectiveDiabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits and the corresponding neurophysiological structural and functional alterations are linked to both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. To elucidate the specific role of brain insulin signalling in neuronal functions that are relevant for cognitive processes we have investigated the behaviour of neurons and synaptic plasticity in the hippocampus of mice lacking the insulin receptor substrate protein 2 (IRS-2).Research Design and MethodsTo study neuronal function and synaptic plasticity in the absence of confounding factors such as hyperglycaemia, we used a mouse model with a central nervous system- (CNS)-restricted deletion of IRS-2 (NesCreIrs2KO).ResultsWe report a deficit in NMDA receptor-dependent synaptic plasticity in the hippocampus of NesCreIrs2KO mice, with a concomitant loss of metaplasticity, the modulation of synaptic plasticity by the previous activity of a synapse. These plasticity changes are associated with reduced basal phosphorylation of the NMDA receptor subunit NR1 and of downstream targets of the PI3K pathway, the protein kinases Akt and GSK-3β.ConclusionsThese findings reveal molecular and cellular mechanisms that might underlie cognitive deficits linked to specific defects of neuronal insulin signalling.

Adolescent female rats exhibiting activity‐based anorexia express elevated levels of GABAA receptor α4 and δ subunits at the plasma membrane of hippocampal CA1 spines

Activity-based anorexia (ABA) is an animal model for anorexia nervosa that has revealed genetic links to anxiety traits and neurochemical characteristics within the hypothalamus. However, few studies have used this animal model to investigate the biological basis for vulnerability of pubertal and adolescent females to ABA, even though the great majority of the anorexia nervosa cases are females exhibiting the first symptoms during puberty. GABAergic inhibition of the hippocampus strongly regulates anxiety as well as plasticity throughout life. We recently showed that the hippocampal CA1 of female mice undergo a dramatic change at puberty onset--from expressing virtually none of the nonsynaptic α4βδ GABA(A) receptors (GABARs) prepubertally to expressing these GABARs at ~7% of the CA1 dendritic spine membranes at puberty onset. Furthermore, we showed that this change underlies the enhanced modulation of anxiety, neuronal excitability, and NMDA receptor-dependent synaptic plasticity in the hippocampus by the stress neurosteroid, THP (3α-OH-5α[β]-pregnan-20-one or [allo]pregnanolone). Here, we used quantitative electron microscopy to determine whether ABA induction in female rats during adolescence also elevates the expression of α4 and δ subunits of α4βδ GABARs, as was observed at puberty onset for mice. Our analysis revealed that rats also exhibit a rise of α4 and δ subunits of α4βδ GABARs at puberty onset, in that these subunits are detectable at ~6% of the dendritic spine membranes of CA1 pyramidal cells at puberty onset (postnatal day 32-36; P32-36) but this drops to about 2% by P40-P44. The levels of α4 and δ subunits at the CA1 spines remained low following exposure of females to either of the two environmental factors needed to generate ABA--food restriction and access to a running wheel for 4 days--from P40 to P44. This pattern contrasted greatly from those of ABA animals, for which the two environmental factors were combined. Within the hippocampus of ABA animals, 12% of the spine profiles were labeled for α4, reflecting a sixfold increase, relative to hippocampi of age-matched (P44) control females (p < 0.005). Concurrently, 7% of the spine profiles were labeled for δ, reflecting a 130% increase from the control values of 3% (p = 0.01). No measurable change was detected for spine size. The observed magnitude of increase in the α4 and δ subunits at spines is sufficient to increase both tonic inhibition of hippocampus and anxiety during stress, thereby likely to exacerbate hyperactivity and weight loss.