GABA-receptive microglia selectively sculpt developing inhibitory circuits.

Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABAB receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.

Top-Down Control of Sweet and Bitter Taste in the Mammalian Brain.

Hardwired circuits encoding innate responses have emerged as an essential feature of the mammalian brain. Sweet and bitter evoke opposing predetermined behaviors. Sweet drives appetitive responses and consumption of energy-rich food sources, whereas bitter prevents ingestion of toxic chemicals. Here we identified and characterized the neurons in the brainstem that transmit sweet and bitter signals from the tongue to the cortex. Next we examined how the brain modulates this hardwired circuit to control taste behaviors. We dissect the basis for bitter-evoked suppression of sweet taste and show that the taste cortex and amygdala exert strong positive and negative feedback onto incoming bitter and sweet signals in the brainstem. Finally we demonstrate that blocking the feedback markedly alters responses to ethologically relevant taste stimuli. These results illustrate how hardwired circuits can be finely regulated by top-down control and reveal the neural basis of an indispensable behavioral response for all animals.

All-Optical Electrophysiology Reveals the Role of Lateral Inhibition in Sensory Processing in Cortical Layer 1.

Cortical layer 1 (L1) interneurons have been proposed as a hub for attentional modulation of underlying cortex, but the transformations that this circuit implements are not known. We combined genetically targeted voltage imaging with optogenetic activation and silencing to study the mechanisms underlying sensory processing in mouse barrel cortex L1. Whisker stimuli evoked precisely timed single spikes in L1 interneurons, followed by strong lateral inhibition. A mild aversive stimulus activated cholinergic inputs and evoked a bimodal distribution of spiking responses in L1. A simple conductance-based model that only contained lateral inhibition within L1 recapitulated the sensory responses and the winner-takes-all cholinergic responses, and the model correctly predicted that the network would function as a spatial and temporal high-pass filter for excitatory inputs. Our results demonstrate that all-optical electrophysiology can reveal basic principles of neural circuit function in vivo and suggest an intuitive picture for how L1 transforms sensory and modulatory inputs. VIDEO ABSTRACT.

Cooperative thalamocortical circuit mechanism for sensory prediction errors.

The brain functions as a prediction machine, utilizing an internal model of the world to anticipate sensations and the outcomes of our actions. Discrepancies between expected and actual events, referred to as prediction errors, are leveraged to update the internal model and guide our attention towards unexpected events1-10. Despite the importance of prediction-error signals for various neural computations across the brain, surprisingly little is known about the neural circuit mechanisms responsible for their implementation. Here we describe a thalamocortical disinhibitory circuit that is required for generating sensory prediction-error signals in mouse primary visual cortex (V1). We show that violating animals' predictions by an unexpected visual stimulus preferentially boosts responses of the layer 2/3 V1 neurons that are most selective for that stimulus. Prediction errors specifically amplify the unexpected visual input, rather than representing non-specific surprise or difference signals about how the visual input deviates from the animal's predictions. This selective amplification is implemented by a cooperative mechanism requiring thalamic input from the pulvinar and cortical vasoactive-intestinal-peptide-expressing (VIP) inhibitory interneurons. In response to prediction errors, VIP neurons inhibit a specific subpopulation of somatostatin-expressing inhibitory interneurons that gate excitatory pulvinar input to V1, resulting in specific pulvinar-driven response amplification of the most stimulus-selective neurons in V1. Therefore, the brain prioritizes unpredicted sensory information by selectively increasing the salience of unpredicted sensory features through the synergistic interaction of thalamic input and neocortical disinhibitory circuits.

Long-range inhibition synchronizes and updates prefrontal task activity.

Changes in patterns of activity within the medial prefrontal cortex enable rodents, non-human primates and humans to update their behaviour to adapt to changes in the environment-for example, during cognitive tasks1-5. Parvalbumin-expressing inhibitory neurons in the medial prefrontal cortex are important for learning new strategies during a rule-shift task6-8, but the circuit interactions that switch prefrontal network dynamics from maintaining to updating task-related patterns of activity remain unknown. Here we describe a mechanism that links parvalbumin-expressing neurons, a new callosal inhibitory connection, and changes in task representations. Whereas nonspecifically inhibiting all callosal projections does not prevent mice from learning rule shifts or disrupt the evolution of activity patterns, selectively inhibiting only callosal projections of parvalbumin-expressing neurons impairs rule-shift learning, desynchronizes the gamma-frequency activity that is necessary for learning8 and suppresses the reorganization of prefrontal activity patterns that normally accompanies rule-shift learning. This dissociation reveals how callosal parvalbumin-expressing projections switch the operating mode of prefrontal circuits from maintenance to updating by transmitting gamma synchrony and gating the ability of other callosal inputs to maintain previously established neural representations. Thus, callosal projections originating from parvalbumin-expressing neurons represent a key circuit locus for understanding and correcting the deficits in behavioural flexibility and gamma synchrony that have been implicated in schizophrenia and related conditions9,10.

Mechanisms of inhibition and activation of extrasynaptic αß GABAA receptors.

Type A GABA (γ-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of α-, ß-, γ-, δ-, ε-, ρ-, θ- and π-subunits1. αß, α4ßδ, α6ßδ and α5ßγ receptors favour extrasynaptic localization, and mediate an essential persistent (tonic) inhibitory conductance in many regions of the mammalian brain1,2. Mutations of these receptors in humans are linked to epilepsy and insomnia3,4. Altered extrasynaptic receptor function is implicated in insomnia, stroke and Angelman and Fragile X syndromes1,5, and drugs targeting these receptors are used to treat postpartum depression6. Tonic GABAergic responses are moderated to avoid excessive suppression of neuronal communication, and can exhibit high sensitivity to Zn2+ blockade, in contrast to synapse-preferring α1ßγ, α2ßγ and α3ßγ receptor responses5,7-12. Here, to resolve these distinctive features, we determined structures of the predominantly extrasynaptic αß GABAA receptor class. An inhibited state bound by both the lethal paralysing agent α-cobratoxin13 and Zn2+ was used in comparisons with GABA-Zn2+ and GABA-bound structures. Zn2+ nullifies the GABA response by non-competitively plugging the extracellular end of the pore to block chloride conductance. In the absence of Zn2+, the GABA signalling response initially follows the canonical route until it reaches the pore. In contrast to synaptic GABAA receptors, expansion of the midway pore activation gate is limited and it remains closed, reflecting the intrinsic low efficacy that characterizes the extrasynaptic receptor. Overall, this study explains distinct traits adopted by αß receptors that adapt them to a role in tonic signalling.

Functional networks of inhibitory neurons orchestrate synchrony in the hippocampus.

Inhibitory interneurons are pivotal components of cortical circuits. Beyond providing inhibition, they have been proposed to coordinate the firing of excitatory neurons within cell assemblies. While the roles of specific interneuron subtypes have been extensively studied, their influence on pyramidal cell synchrony in vivo remains elusive. Employing an all-optical approach in mice, we simultaneously recorded hippocampal interneurons and pyramidal cells and probed the network influence of individual interneurons using optogenetics. We demonstrate that CA1 interneurons form a functionally interconnected network that promotes synchrony through disinhibition during awake immobility, while preserving endogenous cell assemblies. Our network model underscores the importance of both cell assemblies and dense, unspecific interneuron connectivity in explaining our experimental findings, suggesting that interneurons may operate not only via division of labor but also through concerted activity.

Fast-spiking interneuron detonation drives high-fidelity inhibition in the olfactory bulb.

Inhibitory circuits in the mammalian olfactory bulb (OB) dynamically reformat olfactory information as it propagates from peripheral receptors to downstream cortex. To gain mechanistic insight into how specific OB interneuron types support this sensory processing, we examine unitary synaptic interactions between excitatory mitral and tufted cells (MTCs), the OB projection neurons, and a conserved population of anaxonic external plexiform layer interneurons (EPL-INs) using pair and quartet whole-cell recordings in acute mouse brain slices. Physiological, morphological, neurochemical, and synaptic analyses divide EPL-INs into distinct subtypes and reveal that parvalbumin-expressing fast-spiking EPL-INs (FSIs) perisomatically innervate MTCs with release-competent dendrites and synaptically detonate to mediate fast, short-latency recurrent and lateral inhibition. Sparse MTC synchronization supralinearly increases this high-fidelity inhibition, while sensory afferent activation combined with single-cell silencing reveals that individual FSIs account for a substantial fraction of total network-driven MTC lateral inhibition. OB output is thus powerfully shaped by detonation-driven high-fidelity perisomatic inhibition.

Striatal indirect pathway mediates exploration via collicular competition.

The ability to suppress actions that lead to a negative outcome and explore alternative actions is necessary for optimal decision making. Although the basal ganglia have been implicated in these processes1-5, the circuit mechanisms underlying action selection and exploration remain unclear. Here, using a simple lateralized licking task, we show that indirect striatal projection neurons (iSPN) in the basal ganglia contribute to these processes through modulation of the superior colliculus (SC). Optogenetic activation of iSPNs suppresses contraversive licking and promotes ipsiversive licking. Activity in lateral superior colliculus (lSC), a region downstream of the basal ganglia, is necessary for task performance and predicts lick direction. Furthermore, iSPN activation suppresses ipsilateral lSC, but surprisingly excites contralateral lSC, explaining the emergence of ipsiversive licking. Optogenetic inactivation reveals inter-collicular competition whereby each hemisphere of the superior colliculus inhibits the other, thus allowing the indirect pathway to disinhibit the contralateral lSC and trigger licking. Finally, inactivating iSPNs impairs suppression of devalued but previously rewarded licking and reduces exploratory licking. Our results reveal that iSPNs engage the competitive interaction between lSC hemispheres to trigger a motor action and suggest a general circuit mechanism for exploration during action selection.

Inhibitory stabilization and cortical computation.

Neuronal networks with strong recurrent connectivity provide the brain with a powerful means to perform complex computational tasks. However, high-gain excitatory networks are susceptible to instability, which can lead to runaway activity, as manifested in pathological regimes such as epilepsy. Inhibitory stabilization offers a dynamic, fast and flexible compensatory mechanism to balance otherwise unstable networks, thus enabling the brain to operate in its most efficient regimes. Here we review recent experimental evidence for the presence of such inhibition-stabilized dynamics in the brain and discuss their consequences for cortical computation. We show how the study of inhibition-stabilized networks in the brain has been facilitated by recent advances in the technological toolbox and perturbative techniques, as well as a concomitant development of biologically realistic computational models. By outlining future avenues, we suggest that inhibitory stabilization can offer an exemplary case of how experimental neuroscience can progress in tandem with technology and theory to advance our understanding of the brain.

Innate and plastic mechanisms for maternal behaviour in auditory cortex.

Infant cries evoke powerful responses in parents1-4. Whether parental animals are intrinsically sensitive to neonatal vocalizations, or instead learn about vocal cues for parenting responses is unclear. In mice, pup-naive virgin females do not recognize the meaning of pup distress calls, but retrieve isolated pups to the nest after having been co-housed with a mother and litter5-9. Distress calls are variable, and require co-caring virgin mice to generalize across calls for reliable retrieval10,11. Here we show that the onset of maternal behaviour in mice results from interactions between intrinsic mechanisms and experience-dependent plasticity in the auditory cortex. In maternal females, calls with inter-syllable intervals (ISIs) from 75 to 375 milliseconds elicited pup retrieval, and cortical responses were generalized across these ISIs. By contrast, naive virgins were neuronally and behaviourally sensitized to the most common ('prototypical') ISIs. Inhibitory and excitatory neural responses were initially mismatched in the cortex of naive mice, with untuned inhibition and overly narrow excitation. During co-housing experiments, excitatory responses broadened to represent a wider range of ISIs, whereas inhibitory tuning sharpened to form a perceptual boundary. We presented synthetic calls during co-housing and observed that neurobehavioural responses adjusted to match these statistics, a process that required cortical activity and the hypothalamic oxytocin system. Neuroplastic mechanisms therefore build on an intrinsic sensitivity in the mouse auditory cortex, and enable rapid plasticity for reliable parenting behaviour.

Neural Circuits Underlying Multifeature Extraction in the Retina.

Classic ON-OFF direction-selective ganglion cells (DSGCs) that encode the four cardinal directions were recently shown to also be orientation-selective. To clarify the mechanisms underlying orientation selectivity, we employed a variety of electrophysiological, optogenetic, and gene knock-out strategies to test the relative contributions of glutamate, GABA, and acetylcholine (ACh) input that are known to drive DSGCs, in male and female mouse retinas. Extracellular spike recordings revealed that DSGCs respond preferentially to either vertical or horizontal bars, those that are perpendicular to their preferred-null motion axes. By contrast, the glutamate input to all four DSGC types measured using whole-cell patch-clamp techniques was found to be tuned along the vertical axis. Tuned glutamatergic excitation was heavily reliant on type 5A bipolar cells, which appear to be electrically coupled via connexin 36 containing gap junctions to the vertically oriented processes of wide-field amacrine cells. Vertically tuned inputs are transformed by the GABAergic/cholinergic "starburst" amacrine cells (SACs), which are critical components of the direction-selective circuit, into distinct patterns of inhibition and excitation. Feed-forward SAC inhibition appears to "veto" preferred orientation glutamate excitation in dorsal/ventral (but not nasal/temporal) coding DSGCs "flipping" their orientation tuning by 90° and accounts for the apparent mismatch between glutamate input tuning and the DSGC's spiking response. Together, these results reveal how two distinct synaptic motifs interact to generate complex feature selectivity, shedding light on the intricate circuitry that underlies visual processing in the retina.

CCK+ Interneurons Contribute to Thalamus-Evoked Feed-Forward Inhibition in the Prelimbic Prefrontal Cortex.

Interneurons in the medial prefrontal cortex (PFC) regulate local neural activity to influence cognitive, motivated, and emotional behaviors. Parvalbumin-expressing (PV+) interneurons are the primary mediators of thalamus-evoked feed-forward inhibition across the mouse cortex, including the anterior cingulate cortex, where they are engaged by inputs from the mediodorsal (MD) thalamus. In contrast, in the adjacent prelimbic (PL) cortex, we find that PV+ interneurons are scarce in the principal thalamorecipient layer 3 (L3), suggesting distinct mechanisms of inhibition. To identify the interneurons that mediate MD-evoked inhibition in PL, we combine slice physiology, optogenetics, and intersectional genetic tools in mice of both sexes. We find interneurons expressing cholecystokinin (CCK+) are abundant in L3 of PL, with cells exhibiting fast-spiking (fs) or non-fast-spiking (nfs) properties. MD inputs make stronger connections onto fs-CCK+ interneurons, driving them to fire more readily than nearby L3 pyramidal cells and other interneurons. CCK+ interneurons in turn make inhibitory, perisomatic connections onto L3 pyramidal cells, where they exhibit cannabinoid 1 receptor (CB1R) mediated modulation. Moreover, MD-evoked feed-forward inhibition, but not direct excitation, is also sensitive to CB1R modulation. Our findings indicate that CCK+ interneurons contribute to MD-evoked inhibition in PL, revealing a mechanism by which cannabinoids can modulate MD-PFC communication.

Optogenetic Inhibition of Rat Anterior Cingulate Cortex Impairs the Ability to Initiate and Stay on Task.

Our prior research has identified neural correlates of cognitive control in the anterior cingulate cortex (ACC), leading us to hypothesize that the ACC is necessary for increasing attention as rats flexibly learn new contingencies during a complex reward-guided decision-making task. Here, we tested this hypothesis by using optogenetics to transiently inhibit the ACC, while rats of either sex performed the same two-choice task. ACC inhibition had a profound impact on behavior that extended beyond deficits in attention during learning when expected outcomes were uncertain. We found that ACC inactivation slowed and reduced the number of trials rats initiated and impaired both their accuracy and their ability to complete sessions. Furthermore, drift-diffusion model analysis suggested that free-choice performance and evidence accumulation (i.e., reduced drift rates) were degraded during initial learning-leading to weaker associations that were more easily overridden in later trial blocks (i.e., stronger bias). Together, these results suggest that in addition to attention-related functions, the ACC contributes to the ability to initiate trials and generally stay on task.

Inhibitory Subpopulations in preBötzinger Complex Play Distinct Roles in Modulating Inspiratory Rhythm and Pattern.

Inhibitory neurons embedded within mammalian neural circuits shape breathing, walking, and other rhythmic motor behaviors. At the core of the neural circuit controlling breathing is the preBötzinger Complex (preBötC), where GABAergic (GAD1/2+) and glycinergic (GlyT2+) neurons are functionally and anatomically intercalated among glutamatergic Dbx1-derived (Dbx1+) neurons that generate rhythmic inspiratory drive. The roles of these preBötC inhibitory neurons in breathing remain unclear. We first characterized the spatial distribution of molecularly defined preBötC inhibitory subpopulations in male and female neonatal double reporter mice expressing either tdTomato or EGFP in GlyT2+, GAD1+, or GAD2+ neurons. We found that the majority of preBötC inhibitory neurons expressed both GlyT2 and GAD2 while a much smaller subpopulation also expressed GAD1. To determine the functional role of these subpopulations, we used holographic photostimulation, a patterned illumination technique, in rhythmically active medullary slices from neonatal Dbx1tdTomato;GlyT2EGFP and Dbx1tdTomato;GAD1EGFP double reporter mice of either sex. Stimulation of 4 or 8 preBötC GlyT2+ neurons during endogenous rhythm prolonged the interburst interval in a phase-dependent manner and increased the latency to burst initiation when bursts were evoked by stimulation of Dbx1+ neurons. In contrast, stimulation of 4 or 8 preBötC GAD1+ neurons did not affect interburst interval or latency to burst initiation. Instead, photoactivation of GAD1+ neurons during the inspiratory burst prolonged endogenous and evoked burst duration and decreased evoked burst amplitude. We conclude that GlyT2+/GAD2+ neurons modulate breathing rhythm by delaying burst initiation while a smaller GAD1+ subpopulation shapes inspiratory patterning by altering burst duration and amplitude.

Fast Inhibition Slows and Desynchronizes Mouse Auditory Efferent Neuron Activity.

The encoding of acoustic stimuli requires precise neuron timing. Auditory neurons in the cochlear nucleus (CN) and brainstem are well suited for accurate analysis of fast acoustic signals, given their physiological specializations of fast membrane time constants, fast axonal conduction, and reliable synaptic transmission. The medial olivocochlear (MOC) neurons that provide efferent inhibition of the cochlea reside in the ventral brainstem and participate in these fast neural circuits. However, their modulation of cochlear function occurs over time scales of a slower nature. This suggests the presence of mechanisms that reduce MOC inhibition of cochlear function. To determine how monaural excitatory and inhibitory synaptic inputs integrate to affect the timing of MOC neuron activity, we developed a novel in vitro slice preparation ("wedge-slice"). The wedge-slice maintains the ascending auditory nerve root, the entire CN and projecting axons, while preserving the ability to perform visually guided patch-clamp electrophysiology recordings from genetically identified MOC neurons. The "in vivo-like" timing of the wedge-slice demonstrates that the inhibitory pathway accelerates relative to the excitatory pathway when the ascending circuit is intact, and the CN portion of the inhibitory circuit is precise enough to compensate for reduced precision in later synapses. When combined with machine learning PSC analysis and computational modeling, we demonstrate a larger suppression of MOC neuron activity when the inhibition occurs with in vivo-like timing. This delay of MOC activity may ensure that the MOC system is only engaged by sustained background sounds, preventing a maladaptive hypersuppression of cochlear activity.

Essential Role of Latrophilin-1 Adhesion GPCR Nanoclusters in Inhibitory Synapses.

Latrophilin-1 (Lphn1, aka CIRL1 and CL1; gene symbol Adgrl1) is an adhesion GPCR that has been implicated in excitatory synaptic transmission as a candidate receptor for α-latrotoxin. Here we analyzed conditional knock-in/knock-out mice for Lphn1 that contain an extracellular myc epitope tag. Mice of both sexes were used in all experiments. Surprisingly, we found that Lphn1 is localized in cultured neurons to synaptic nanoclusters that are present in both excitatory and inhibitory synapses. Conditional deletion of Lphn1 in cultured neurons failed to elicit a detectable impairment in excitatory synapses but produced a decrease in inhibitory synapse numbers and synaptic transmission that was most pronounced for synapses close to the neuronal soma. No changes in axonal or dendritic outgrowth or branching were observed. Our data indicate that Lphn1 is among the few postsynaptic adhesion molecules that are present in both excitatory and inhibitory synapses and that Lphn1 by itself is not essential for excitatory synaptic transmission but is required for some inhibitory synaptic connections.

Hypothalamic Paraventricular Stimulation Inhibits Nociceptive Wide Dynamic Range Trigeminocervical Complex Cells via Oxytocinergic Transmission.

Oxytocinergic transmission blocks nociception at the peripheral, spinal, and supraspinal levels through the oxytocin receptor (OTR). Indeed, a neuronal pathway from the hypothalamic paraventricular nucleus (PVN) to the spinal cord and trigeminal nucleus caudalis (Sp5c) has been described. Hence, although the trigeminocervical complex (TCC), an anatomical area spanning the Sp5c, C1, and C2 regions, plays a role in some pain disorders associated with craniofacial structures (e.g., migraine), the role of oxytocinergic transmission in modulating nociception at this level has been poorly explored. Hence, in vivo electrophysiological recordings of TCC wide dynamic range (WDR) cells sensitive to stimulation of the periorbital or meningeal region were performed in male Wistar rats. PVN electrical stimulation diminished the neuronal firing evoked by periorbital or meningeal electrical stimulation; this inhibition was reversed by OTR antagonists administered locally. Accordingly, neuronal projections (using Fluoro-Ruby) from the PVN to the WDR cells filled with Neurobiotin were observed. Moreover, colocalization between OTR and calcitonin gene-related peptide (CGRP) or OTR and GABA was found near Neurobiotin-filled WDR cells. Retrograde neuronal tracers deposited at the meningeal (True-Blue, TB) and infraorbital nerves (Fluoro-Gold, FG) showed that at the trigeminal ganglion (TG), some cells were immunopositive to both fluorophores, suggesting that some TG cells send projections via the V1 and V2 trigeminal branches. Together, these data may imply that endogenous oxytocinergic transmission inhibits the nociceptive activity of second-order neurons via OTR activation in CGRPergic (primary afferent fibers) and GABAergic cells.

Optogenetic Determination of Dynamic and Cell-Type-Specific Inhibitory Reversal Potentials.

The reversal potential refers to the membrane potential at which the net current flow through a channel reverses direction. The reversal potential is determined by transmembrane ion gradients and, in turn, determines how the channel's activity will affect the membrane potential. Traditional investigation into the reversal potential of inhibitory ligand-gated ion channels (EInh) has relied upon the activation of endogenous receptors, such as the GABA-A receptor (GABAAR). There are, however, challenges associated with activating endogenous receptors, including agonist delivery, isolating channel responses, and the effects of receptor saturation and desensitization. Here, we demonstrate the utility of using a light-gated anion channel, stGtACR2, to probe EInh in the rodent brain. Using mice of both sexes, we demonstrate that the properties of this optically activated channel make it a suitable proxy for studying GABAAR receptor-mediated inhibition. We validate this agonist-independent optogenetic strategy in vitro and in vivo and further show how it can accurately capture differences in EInh dynamics following manipulations of endogenous ion fluxes. This allows us to explore distinct resting EInh differences across genetically defined neuronal subpopulations. Using this approach to challenge ion homeostasis mechanisms in neurons, we uncover cell-specific EInh dynamics that are supported by the differential expression of endogenous ion handling mechanisms. Our findings therefore establish an effective optical strategy for revealing novel aspects of inhibitory reversal potentials and thereby expand the repertoire of optogenetics.

TRPM2 and CaMKII Signaling Drives Excessive GABAergic Synaptic Inhibition Following Ischemia.

Excitotoxicity and the concurrent loss of inhibition are well-defined mechanisms driving acute elevation in excitatory/inhibitory (E/I) balance and neuronal cell death following an ischemic insult to the brain. Despite the high prevalence of long-term disability in survivors of global cerebral ischemia (GCI) as a consequence of cardiac arrest, it remains unclear whether E/I imbalance persists beyond the acute phase and negatively affects functional recovery. We previously demonstrated sustained impairment of long-term potentiation (LTP) in hippocampal CA1 neurons correlating with deficits in learning and memory tasks in a murine model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Here, we use CA/CPR and an in vitro ischemia model to elucidate mechanisms by which E/I imbalance contributes to ongoing hippocampal dysfunction in male mice. We reveal increased postsynaptic GABAA receptor (GABAAR) clustering and function in the CA1 region of the hippocampus that reduces the E/I ratio. Importantly, reduced GABAAR clustering observed in the first 24 h rebounds to an elevation of GABAergic clustering by 3 d postischemia. This increase in GABAergic inhibition required activation of the Ca2+-permeable ion channel transient receptor potential melastatin-2 (TRPM2), previously implicated in persistent LTP and memory deficits following CA/CPR. Furthermore, we find Ca2+-signaling, likely downstream of TRPM2 activation, upregulates Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, thereby driving the elevation of postsynaptic inhibitory function. Thus, we propose a novel mechanism by which inhibitory synaptic strength is upregulated in the context of ischemia and identify TRPM2 and CaMKII as potential pharmacological targets to restore perturbed synaptic plasticity and ameliorate cognitive function.