A Cold-Sensing Receptor Encoded by a Glutamate Receptor Gene.

In search of the molecular identities of cold-sensing receptors, we carried out an unbiased genetic screen for cold-sensing mutants in C. elegans and isolated a mutant allele of glr-3 gene that encodes a kainate-type glutamate receptor. While glutamate receptors are best known to transmit chemical synaptic signals in the CNS, we show that GLR-3 senses cold in the peripheral sensory neuron ASER to trigger cold-avoidance behavior. GLR-3 transmits cold signals via G protein signaling independently of its glutamate-gated channel function, suggesting GLR-3 as a metabotropic cold receptor. The vertebrate GLR-3 homolog GluK2 from zebrafish, mouse, and human can all function as a cold receptor in heterologous systems. Mouse DRG sensory neurons express GluK2, and GluK2 knockdown in these neurons suppresses their sensitivity to cold but not cool temperatures. Our study identifies an evolutionarily conserved cold receptor, revealing that a central chemical receptor unexpectedly functions as a thermal receptor in the periphery.

The neural circuits and synaptic mechanisms underlying motor initiation in C. elegans.

C. elegans is widely used to dissect how neural circuits and genes generate behavior. During locomotion, worms initiate backward movement to change locomotion direction spontaneously or in response to sensory cues; however, the underlying neural circuits are not well defined. We applied a multidisciplinary approach to map neural circuits in freely behaving worms by integrating functional imaging, optogenetic interrogation, genetic manipulation, laser ablation, and electrophysiology. We found that a disinhibitory circuit and a stimulatory circuit together promote initiation of backward movement and that circuitry dynamics is differentially regulated by sensory cues. Both circuits require glutamatergic transmission but depend on distinct glutamate receptors. This dual mode of motor initiation control is found in mammals, suggesting that distantly related organisms with anatomically distinct nervous systems may adopt similar strategies for motor control. Additionally, our studies illustrate how a multidisciplinary approach facilitates dissection of circuit and synaptic mechanisms underlying behavior in a genetic model organism.

Brain-gut communications via distinct neuroendocrine signals bidirectionally regulate longevity in C. elegans.

Tissue-tissue communications are integral to organismal aging, orchestrating a body-wide aging process. The brain plays a key role in this process by detecting and processing signals from the environment and then communicating them to distal tissues such as the gut to regulate longevity. How this is achieved, however, is poorly understood. Here, using Caenorhabditis elegans as a model, we identified two distinct neuroendocrine signaling circuits by which the worm nervous system senses cool and warm environmental temperatures through cool- and warm-sensitive neurons and then signals the gut to extend and shorten life span, respectively. The prolongevity "cool" circuit uses the small neurotransmitters glutamate and serotonin, whereas the anti-longevity "warm" circuit is mediated by insulin-like neuropeptides. Both types of neuroendocrine signals converge on the gut through their cognate receptors to differentially regulate the transcription factor DAF-16/FOXO, leading to opposing outcomes in longevity. Our study illustrates how the brain detects and processes environmental signals to bidirectionally regulate longevity by signaling the gut.

Regulation of Synapse Weakening through Interactions of the Microtubule Associated Protein Tau with PACSIN1.

Hyperphosphorylation of the microtubule associated protein tau (tau) is inextricably linked to several neurodegenerative diseases, collectively termed tauopathies, in which synapse dysfunction occurs through largely unidentified mechanisms. Our research aimed to uncover molecular mechanisms by which phosphorylation of tau (pTau) affects synapse function. Using combined molecular and electrophysiological analysis with in vitro genetic knock-in of phosphorylation mutant human tau in male rat CA1 hippocampal neurons, we show an interplay between tau and protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1) that regulates synapse function. pTau at serine residues 396/404 decreases tau:PACSIN1 binding and evokes PACSIN1-dependent functional and structural synapse weakening. Knock-down of tau or PACSIN1 increases AMPA receptor (AMPAR)-mediated current at extrasynaptic regions, supporting a role for these proteins in affecting AMPAR trafficking. The pTau-induced PACSIN1 dissociation may represent a pathophysiological regulator of synapse function that underlies tauopathy-associated synapse defects.SIGNIFICANCE STATEMENT Knowledge is still lacking for how hyperphosphorylation of tau and its effectors lead to synaptic and neuronal dysfunction. Our results provide crucial insight for this mechanistic understanding; we show that specific tau phosphorylation events modulate its protein interaction with PACSIN1 and thus elicits synapse weakening likely through PACSIN1-dependent regulation of AMPA receptor (AMPAR) trafficking. These findings develop our understanding of molecular events that may be relevant to cellular changes underpinning tauopathy-associated neurodegenerative diseases.

RAB39B-mediated trafficking of the GluA2-AMPAR subunit controls dendritic spine maturation and intellectual disability-related behaviour.

Mutations in the RAB39B gene cause X-linked intellectual disability (XLID), comorbid with autism spectrum disorders or early Parkinson's disease. One of the functions of the neuronal small GTPase RAB39B is to drive GluA2/GluA3 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) maturation and trafficking, determining AMPAR subunit composition at glutamatergic postsynaptic neuronal terminals. Taking advantage of the Rab39b knockout murine model, we show that a lack of RAB39B affects neuronal dendritic spine refinement, prompting a more Ca2+-permeable and excitable synaptic network, which correlates with an immature spine arrangement and behavioural and cognitive alterations in adult mice. The persistence of immature circuits is triggered by increased hypermobility of the spine, which is restored by the Ca2+-permeable AMPAR antagonist NASPM. Together, these data confirm that RAB39B controls AMPAR trafficking, which in turn plays a pivotal role in neuronal dendritic spine remodelling and that targeting Ca2+-permeable AMPARs may highlight future pharmaceutical interventions for RAB39B-associated disease conditions.

Modelling the spatial and temporal constrains of the GABAergic influence on neuronal excitability.

GABA (γ-amino butyric acid) is an inhibitory neurotransmitter in the adult brain that can mediate depolarizing responses during development or after neuropathological insults. Under which conditions GABAergic membrane depolarizations are sufficient to impose excitatory effects is hard to predict, as shunting inhibition and GABAergic effects on spatiotemporal filtering of excitatory inputs must be considered. To evaluate at which reversal potential a net excitatory effect was imposed by GABA (EGABAThr), we performed a detailed in-silico study using simple neuronal topologies and distinct spatiotemporal relations between GABAergic and glutamatergic inputs. These simulations revealed for GABAergic synapses located at the soma an EGABAThr close to action potential threshold (EAPThr), while with increasing dendritic distance EGABAThr shifted to positive values. The impact of GABA on AMPA-mediated inputs revealed a complex temporal and spatial dependency. EGABAThr depends on the temporal relation between GABA and AMPA inputs, with a striking negative shift in EGABAThr for AMPA inputs appearing after the GABA input. The spatial dependency between GABA and AMPA inputs revealed a complex profile, with EGABAThr being shifted to values negative to EAPThr for AMPA synapses located proximally to the GABA input, while for distally located AMPA synapses the dendritic distance had only a minor effect on EGABAThr. For tonic GABAergic conductances EGABAThr was negative to EAPThr over a wide range of gGABAtonic values. In summary, these results demonstrate that for several physiologically relevant situations EGABAThr is negative to EAPThr, suggesting that depolarizing GABAergic responses can mediate excitatory effects even if EGABA did not reach EAPThr.

A hierarchy of manganese competition and entry in organotypic hippocampal slice cultures.

Contrast agents improve clinical and basic research MRI. The manganese ion (Mn2+ ) is an essential, endogenous metal found in cells and it enhances MRI contrast because of its paramagnetic properties. Manganese-enhanced MRI (MEMRI) has been widely used to image healthy and diseased states of the body and the brain in a variety of animal models. There has also been some work in translating the useful properties of MEMRI to humans. Mn2+ accumulates in brain regions with high neural activity and enters cells via voltage-dependent channels that flux calcium (Ca2+ ). In addition, metal transporters for zinc (Zn2+ ) and iron (Fe2+ ) can also transport Mn2+ . There is also transfer through channels specific for Mn2+ . Although Mn2+ accumulates in many tissues including brain, the mechanisms and preferences of its mode of entry into cells are not well characterized. The current study used MRI on living organotypic hippocampal slice cultures to detect which transport mechanisms are preferentially used by Mn2+ to enter cells. The use of slice culture overcomes the presence of the blood brain barrier, which limits inferences made with studies of the intact brain in vivo. A range of Mn2+ concentrations were used and their effects on neural activity were assessed to avoid using interfering doses of Mn2+ . Zn2+ and Fe2+ were the most efficient competitors for Mn2+ uptake into the cultured slices, while the presence of Ca2+ or Ca2+ channel antagonists had a more moderate effect. Reducing slice activity via excitatory receptor antagonists was also effective at lowering Mn2+ uptake. In conclusion, a hierarchy of those agents which influence Mn2+ uptake was established to enhance understanding of how Mn2+ enters cells in a cultured slice preparation.

Novel rapid-acting glutamatergic modulators: Targeting the synaptic plasticity in depression.

Major depressive disorder (MDD) is severely prevalent, and conventional monoaminergic antidepressants gradually exhibit low therapeutic efficiency, especially for patients with treatment-resistant depression. A neuroplasticity hypothesis is an emerging advancement in the mechanism of depression, mainly expressed in the glutamate system, e.g., glutamate receptors and signaling. Dysfunctional glutamatergic neurotransmission is currently considered to be closely associated with the pathophysiology of MDD. Biological function, pharmacological action, and signal attributes in the glutamate system both regulate the neural process. Specific functional subunits could be therapeutic targets to explore the novel glutamatergic modulators, which have fast-acting, and relatively sustained antidepressant effects. Here, the present review summarizes the pathophysiology of MDD found in the glutamate system, exploring the role of glutamate receptors and their downstream effects. These convergent mechanisms have prompted the development of other modulators targeting on glutamate system, including N-methyl-d-aspartate receptor antagonists, selective GluN2B-specific antagonists, glycine binding site agents, and regulators of metabotropic glutamate receptors. Relevant researches underly the putative mechanisms of these drugs, which reverse the damage of depression by regulating glutamatergic neurotransmission. It also provides further insight into the mechanism of depression and exploring potential targets for novel agent development.

Transcriptional modulation of calcium-permeable AMPA receptor subunits in glioblastoma by MEK-ERK1/2 inhibitors and their role in invasion.

Glioblastoma is the most common primary brain tumor. Glioblastoma cells secrete a significant amount of glutamate, which serve as a potential growth factor in glioma pathobiology through their specific receptor subtypes including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Glioblastoma express AMPAR subunits; however, its regulation and activation with downstream intracellular signaling are not well-understood. Phosphorylated-extracellular signaling-regulated kinase (ERK)1/2 is known to regulate the ionotropic glutamate receptors in cortical neurons. The mitogen-activated protein kinase cascade is frequently activated in several tumors, including glioma. Nonetheless, the association of ERK signaling with AMPAR subunits in glioblastoma is undetermined. Here, we demonstrated potential role of AMPAR in invasion, and the modulation of AMPAR subunits at transcript level by ERK signaling in glioblastoma cells. Inhibition of ERK signaling specifically downregulated the expression of calcium-permeable AMPAR subunits, GluA1 and GluA4, and upregulated calcium-impermeable AMPAR subunit GluA2 implying differential regulation of the expression of calcium-permeable AMPAR subunits of glioblastoma. Concomitantly, it significantly decreased the invasion of U87MG cells. Taken together, these findings suggest that the AMPAR enhances invasion of glioblastoma, and ERK signaling modulates the differential expression of calcium-permeable AMPAR phenotype that might play a crucial role in the invasive propensity of glioblastoma cells.

The role of glutamate receptors and their interactions with dopamine and other neurotransmitters in the development of tardive dyskinesia: preclinical and clinical results.

Tardive dyskinesia is a serious, disabling, movement disorder associated with the ongoing use of antipsychotic medication. Current evidence regarding the pathophysiology of tardive dyskinesia is mainly based on preclinical animal models and is still not completely understood. The leading preclinical hypothesis of tardive dyskinesia development includes dopaminergic imbalance in the direct and indirect pathways of the basal ganglia, cholinergic deficiency, serotonin receptor disturbances, neurotoxicity, oxidative stress, and changes in synaptic plasticity. Although, the role of the glutamatergic system has been confirmed in preclinical tardive dyskinesia models it seems to have been neglected in recent reviews. This review focuses on the role and interactions of glutamate receptors with dopamine, acetylcholine, and serotonin in the neuropathology of tardive dyskinesia development. Moreover, preclinical and clinical results of the differentiated effectiveness of N-methyl-D-aspartate (NMDA) receptor antagonists are discussed with a special focus on antagonists that bind with the GluN2B subunit of NMDA receptors. This review also presents new combinations of drugs that are worth considering in the treatment of tardive dyskinesia.

Omega-3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses.

Dietary omega-3 fatty acids accumulate and are actively retained in central nervous system membranes, mainly in synapses, dendrites and photoreceptors. Despite this selective enrichment, their impact on synaptic function and plasticity has not been fully determined at the molecular level. In this study, we explored the impact of omega-3 fatty acid deficiency on synaptic function in the hippocampus. Dietary omega-3 fatty acid deficiency for 5 months after weaning led to a 65% reduction in the concentration of docosahexaenoic acid in whole brain synaptosomal phospholipids with no impact on global dopaminergic or serotonergic turnover. We observed reduced concentrations of glutamate receptor subunits, including GluA1, GluA2 and NR2B, and synaptic vesicle proteins synaptophysin and synaptotagmin 1 in hippocampal synaptosomes of omega-3 fatty acid-deficient mice as compared to the omega-3 fatty acid rich group. In contrast, an increased concentration of neuronal inositol 1,4,5-trisphosphate-receptor (IP3 -R) was observed in the deficient group. Furthermore, omega-3 fatty acid deficiency reduced the long-term potentiation (LTP) in stratum oriens of the hippocampal CA1 area, but not in stratum radiatum. Thus, omega-3 fatty acids seem to have specific effects in distinct subsets of glutamatergic synapses, suggesting specific molecular interactions in addition to altering plasma membrane properties on a more global scale.

Disrupted neuronal trafficking in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease caused by degeneration of motor neurons in the brain and spinal cord leading to muscle weakness. Median survival after symptom onset in patients is 3-5 years and no effective therapies are available to treat or cure ALS. Therefore, further insight is needed into the molecular and cellular mechanisms that cause motor neuron degeneration and ALS. Different ALS disease mechanisms have been identified and recent evidence supports a prominent role for defects in intracellular transport. Several different ALS-causing gene mutations (e.g., in FUS, TDP-43, or C9ORF72) have been linked to defects in neuronal trafficking and a picture is emerging on how these defects may trigger disease. This review summarizes and discusses these recent findings. An overview of how endosomal and receptor trafficking are affected in ALS is followed by a description on dysregulated autophagy and ER/Golgi trafficking. Finally, changes in axonal transport and nucleocytoplasmic transport are discussed. Further insight into intracellular trafficking defects in ALS will deepen our understanding of ALS pathogenesis and will provide novel avenues for therapeutic intervention.

GluD1, linked to schizophrenia, controls the burst firing of dopamine neurons.

Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia.

The glutamate receptors AtGLR1.2 and AtGLR1.3 increase cold tolerance by regulating jasmonate signaling in Arabidopsis thaliana.

Plant glutamate-like receptors (GLRs), which are homologs of mammalian ionotropic glutamate receptors (iGluRs), are thought to be involved in plant growth, development, and environmental stress responses. In this study, we demonstrated that two members of Arabidopsis glutamate-like receptors, AtGLR1.2 and AtGLR1.3, play positive roles in the plant response to cold stress. Genetic and biochemical experiments revealed that exogenous jasmonate could attenuate the cold sensitivity of glr1.2 and glr1.3 mutants, and the overexpression of GLR1.2 or GLR1.3 enhanced cold tolerance by increasing endogenous jasmonate levels under cold stress. In addition, the expression of genes in the CBF/DREB1 signaling pathway was decreased in the glr1.2 and glr1.3 mutants, but was promoted in GLR1.2-OE and GLR1.3-OE transgenic plants compared with the wild-type during cold treatment. Further investigation revealed that AtGLR1.2 and AtGLR1.3 independently drove similar functions without directly interacting. Together, our findings suggest that AtGLR1.2 and 1.3 positively enhance cold tolerance in Arabidopsis by activating endogenous jasmonate accumulation and subsequently promoting the downstream CBF/DREB1 cold response pathway during cold stress.

MicroRNA in glutamate receptor-dependent neurological diseases.

Glutamate-mediated excitotoxicity is the major neuropathological process contributing to numerous neurological diseases. Recently, emerging evidence indicates that microRNAs (miRNAs) play essential roles in the pathophysiology of a wide range of neurological diseases. Notably, there have been significant developments in understanding the biogenesis of miRNAs, their regulatory mechanisms, and their potential as effective biomarkers and therapies. In the present review, we summarize the recent literature that highlights the versatile roles played by miRNAs in glutamate receptor (GluR)-dependent neurological diseases. Based on the reported studies to date, modulation of miRNAs could emerge as a promising therapeutic target for a variety of neurological diseases that were discussed in this review.

Ethanol drives aversive conditioning through dopamine 1 receptor and glutamate receptor-mediated activation of lateral habenula neurons.

There has been increasing interest in the lateral habenula (LHb) given its potent regulatory role in many aversion-related behaviors. Interestingly, ethanol can be rewarding as well as aversive; we therefore investigated whether ethanol exposure alters pacemaker firing or glutamate receptor signaling in LHb neurons in vitro and also whether LHb activity in vivo might contribute to the acquisition of conditioned place aversion to ethanol. Surprisingly, in epithalamic slices, low doses of ethanol (1.4 mM) strongly accelerated LHb neuron firing (by ~60%), and ethanol's effects were much reduced by blocking glutamate receptors. Ethanol increased presynaptic glutamate release, and about half of this effect was mediated by dopamine subtype 1 receptors (D1Rs) and cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. In agreement with these findings, c-Fos immunoreactivity in LHb regions was enhanced after a single administration of a low dose of ethanol (0.25 g/kg i.p.). Importantly, the same dose of ethanol in vivo also produced strong conditioned place aversion, and this was prevented by inhibiting D1Rs or neuronal activity within the LHb. By contrast, a higher dose (2 g/kg) led to ethanol conditioned place preference, which was enhanced by inhibiting neuronal activity or D1Rs within the LHb and suppressed by infusing aminomethylphosphonic acid or the D1R agonist SKF38393 within the LHb. Our in vitro and in vivo observations show, for the first time, that ethanol increases LHb excitation, mediated by D1R and glutamate receptors, and may underlie a LHb aversive signal that contributes to ethanol-related aversion.

Functional insights from glutamate receptor ion channel structures.

X-ray crystal structures for the soluble amino-terminal and ligand-binding domains of glutamate receptor ion channels, combined with a 3.6-Å-resolution structure of the full-length AMPA receptor GluA2 homotetramer, provide unique insights into the mechanisms of the assembly and function of glutamate receptor ion channels. Increasingly sophisticated biochemical, computational, and electrophysiological experiments are beginning to reveal the mechanism of action of partial agonists and suggest new models for the mechanism of action of allosteric modulators. Newly identified NMDA receptor ligands acting at novel sites offer hope for the development of subtype-selective modulators. The many unresolved issues include the role of the amino-terminal domain in AMPA receptor signaling and the mechanisms by which auxiliary proteins regulate receptor activity. The structural basis for ion permeation and ion channel block also remain areas of uncertainty, and despite substantial progress, molecular dynamics simulations have yet to reveal how glutamate binding opens the ion channel pore.

Glutamate Receptors within the Mesolimbic Dopamine System Mediate Alcohol Relapse Behavior.

Glutamatergic input within the mesolimbic dopamine (DA) pathway plays a critical role in the development of addictive behavior. Although this is well established for some drugs of abuse, it is not known whether glutamate receptors within the mesolimbic system are involved in mediating the addictive properties of chronic alcohol use. Here we evaluated the contribution of mesolimbic NMDARs and AMPARs in mediating alcohol-seeking responses induced by environmental stimuli and relapse behavior using four inducible mutant mouse lines lacking the glutamate receptor genes Grin1 or Gria1 in either DA transporter (DAT) or D1R-expressing neurons. We first demonstrate the lack of GluN1 or GluA1 in either DAT- or D1R-expressing neurons in our mutant mouse lines by colocalization studies. We then show that GluN1 and GluA1 receptor subunits within these neuronal subpopulations mediate the alcohol deprivation effect, while having no impact on context- plus cue-induced reinstatement of alcohol-seeking behavior. We further validated these results pharmacologically by demonstrating similar reductions in the alcohol deprivation effect after infusion of the NMDAR antagonist memantine into the nucleus accumbens and ventral tegmental area of control mice, and a rescue of the mutant phenotype via pharmacological potentiation of AMPAR activity using aniracetam. In conclusion, dopamine neurons as well as D1R-expressing medium spiny neurons and their glutamatergic inputs via NMDARs and AMPARs act in concert to influence relapse responses. These results provide a neuroanatomical and molecular substrate for relapse behavior and emphasize the importance of glutamatergic drugs in modulating relapse behavior. SIGNIFICANCE STATEMENT: Here we provide genetic and pharmacological evidence that glutamate receptors within the mesolimbic dopamine system play an essential role in alcohol relapse. Using various inducible and site-specific transgenic mouse models and pharmacological validation experiments, we show that critical subunits of NMDARs and AMPARs expressed either in dopamine neurons or in dopamine receptor D1-containing neurons play an important role in the alcohol deprivation effect (the increase in alcohol intake after a period of abstinence) while having no impact on context- plus cue-induced reinstatement of alcohol-seeking responses. Medications targeting glutamatergic neurotransmission by selective inactivation of these glutamate receptors might have therapeutic efficacy.

Dynamic Changes from Depolarizing to Hyperpolarizing GABAergic Actions during Giant Depolarizing Potentials in the Neonatal Rat Hippocampus.

During development, GABA exerts depolarizing action on immature neurons and, acting in synergy with glutamate, drives giant depolarizing potentials (GDPs) in the hippocampal network. Yet, blockade of the GABA(A) receptors transforms GDPs to epileptiform discharges suggesting dual, both excitatory and inhibitory, actions of GABA in the immature hippocampal network. However, the nature of this dualism in early GABA actions is poorly understood. Here we characterized the dynamics of synaptic currents mediated by GABA(A) and glutamate receptors through an estimation of the changes in their conductance and driving forces in neonatal rat CA3 pyramidal cells during GDPs. We found that depolarizing GABAergic and glutamatergic currents act in synergy at the GDPs' onset. However, during the peak of the population discharge, the inward synaptic current was essentially mediated by glutamate receptors whereas GABA currents transiently switched their direction from depolarizing to hyperpolarizing as a result of neuronal depolarization above the GABA(A) reversal potential. Thus, the action of GABA on CA3 pyramidal cells dynamically changes during GDPs from excitatory at the GDPs' onset to inhibitory at the GDPs' peak. We propose that the dynamic changes in GABA actions occurring during GDPs enable GABAergic interneurons not only to initiate the discharge of pyramidal cells but also to control excitation in the recurrent CA3 network preventing epileptiform synchronization. SIGNIFICANCE STATEMENT: During development GABA exerts a depolarizing action on immature neurons. However, at the network level the effects of GABA are complex involving both excitatory and inhibitory actions. Here we show that GABA actions critically depend on the network state. Although GABA depolarizes neurons at rest and at the onset of population bursts, it transiently becomes hyperpolarizing at the peak of the population bursts. These dynamic changes in GABA actions enable GABAergic interneurons not only to initiate the network discharge but also to control excitation to prevent epileptiform synchronization.

Dynamic DNA methylation controls glutamate receptor trafficking and synaptic scaling.

Hebbian plasticity, including long-term potentiation and long-term depression, has long been regarded as important for local circuit refinement in the context of memory formation and stabilization. However, circuit development and stabilization additionally relies on non-Hebbian, homeostatic, forms of plasticity such as synaptic scaling. Synaptic scaling is induced by chronic increases or decreases in neuronal activity. Synaptic scaling is associated with cell-wide adjustments in postsynaptic receptor density, and can occur in a multiplicative manner resulting in preservation of relative synaptic strengths across the entire neuron's population of synapses. Both active DNA methylation and demethylation have been validated as crucial regulators of gene transcription during learning, and synaptic scaling is known to be transcriptionally dependent. However, it has been unclear whether homeostatic forms of plasticity such as synaptic scaling are regulated via epigenetic mechanisms. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously largely considered separately: DNA methylation, homeostatic plasticity, and glutamate receptor trafficking. This review describes exciting recent work that has demonstrated a role for active changes in neuronal DNA methylation and demethylation as a controller of synaptic scaling and glutamate receptor trafficking. These findings bring together three major categories of memory-associated mechanisms that were previously considered separately: glutamate receptor trafficking, DNA methylation, and homeostatic plasticity.