AMPA Research Articles

Cell‐Specific Optical Control of AMPA Glutamate Receptors with a Photoswitchable Tethered Antagonist

AbstractAMPA receptors (AMPARs) are the main drivers of excitatory glutamatergic transmission in the brain, central to synaptic plasticity, and are key drug targets. However, AMPARs are expressed in virtually every neuron in the central nervous system and are activated with complex temporal dynamics, making it difficult to determine their functional roles with sufficient precision. Here we describe a cell specific, light‐controllable competitive antagonist for the AMPA receptor called MP‐GluAblock that combines the temporal precision of a photo‐switchable ligand with the spatial and cellular specificity of a genetically‐encoded membrane‐anchor protein. This tool could pave the way for controlling endogenous AMPARs in neural circuits with cellular, spatial, and temporal specificity.

Cell-Specific Optical Control of AMPA Glutamate Receptors with a Photoswitchable Tethered Antagonist.

AMPA receptors (AMPARs) are the main drivers of excitatory glutamatergic transmission in the brain, central to synaptic plasticity, and are key drug targets. However, AMPARs are expressed in virtually every neuron in the central nervous system and are activated with complex temporal dynamics, making it difficult to determine their functional roles with sufficient precision. Here we describe a cell specific, light-controllable competitive antagonist for the AMPA receptor called MP-GluAblock that combines the temporal precision of a photo-switchable ligand with the spatial and cellular specificity of a genetically-encoded membrane-anchor protein. This tool could pave the way for controlling endogenous AMPARs in neural circuits with cellular, spatial, and temporal specificity.

Pubertal- and Stress-Dependent Changes in Cellular Activation and Expression of Excitatory Amino Acid Receptor Subunits in the Paraventricular Nucleus of the Hypothalamus in Male and Female Rats

Introduction: Pubertal maturation is marked by significant changes in stress-induced hormonal responses mediated by the hypothalamic-pituitary-adrenal (HPA) axis, with prepubertal male and female rats often exhibiting greater HPA reactivity compared to adult males and females. Though the implications of these changes are unclear, elevated stress responsiveness might contribute to the stress-related vulnerabilities often associated with puberty. Methods: The current experiments sought to determine whether differences in cellular activation, as measured by FOS immunohistochemistry, or excitatory ionotropic glutamate receptor subunit expression, as measured by qRT-PCR, in the paraventricular nucleus (PVN) were associated with these noted pubertal shifts in stress reactivity in male and female rats. As the PVN is the key nucleus responsible for activating the hormonal stress response, we predicted greater cellular activation and higher expression levels of glutamate receptor subunits in the PVN of prepubertal males and females compared to their adult counterparts. Results: Our FOS data revealed that while prepubertal males showed greater stress-induced activation in the PVN than adult males, prepubertal females showed less activation than adult females. Moreover, many of the NMDA, AMPA, and kainate receptor subunits measured, including Grin1, Grin2b, Gria1, Gria2, Grik1, and Grik2, had higher expression levels in adults, particularly in males. Conclusions: Though not supporting our initial predictions, these data do indicate that age and stress influence the activation of the PVN and the expression of glutamate receptor subunits important in its function. These data also suggest that the effects of age and stress are different in males and females. Though still far from a clear understanding of what mechanism(s) mediate pubertal shift in stress reactivity, these data add to our growing understanding of how age, stress, and sex influence HPA function.

CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability.

Haploinsufficiency of the CACNA1A gene, encoding the pore-forming α1 subunit of P/Q-type voltage-gated calcium channels, is associated with a clinically variable phenotype ranging from cerebellar ataxia, to neurodevelopmental syndromes with epilepsy and intellectual disability. To understand the pathological mechanisms of CACNA1A loss-of-function variants, we characterized a human neuronal model for CACNA1A haploinsufficiency, by differentiating isogenic induced pluripotent stem cell lines into glutamatergic neurons, and investigated the effect of CACNA1A haploinsufficiency on mature neuronal networks through a combination of electrophysiology, gene expression analysis, and in silico modeling. We observed an altered network synchronization in CACNA1A+/- networks alongside synaptic deficits, notably marked by an augmented contribution of GluA2-lacking AMPA receptors. Intriguingly, these synaptic perturbations coexisted with increased non-synaptically driven activity, as characterized by inhibition of NMDA and AMPA receptors on micro-electrode arrays. Single-cell electrophysiology and gene expression analysis corroborated this increased intrinsic excitability through reduced potassium channel function and expression. Moreover, we observed partial mitigation of the CACNA1A+/- network phenotype by 4-aminopyridine, a therapeutic intervention for episodic ataxia type 2. Positive modulation of KCa2 channels could reverse the CACNA1A+/- network electrophysiological phenotype. In summary, our study pioneers the characterization of a human induced pluripotent stem cell-derived neuronal model for CACNA1A haploinsufficiency, and has unveiled novel mechanistic insights. Beyond showcasing synaptic deficits, this neuronal model exhibited increased intrinsic excitability mediated by diminished potassium channel function, underscoring its potential as a therapeutic discovery platform with predictive validity.

Prenatal ethanol exposure impairs hippocampal plasticity and cognition in adolescent mice

BackgroundPrenatal alcohol exposure (PAE) induces a wide range of neurodevelopmental disabilities that are grouped under the term ‘fetal alcohol spectrum disorders’ (FASD). The effects of PAE on brain development are dependent on complex neurochemical events, including modification of AMPA receptors (AMPARs). We have recently found that chronic ethanol (EtOH) exposure decreases AMPA-mediated neurotransmission and expression through the overexpression of the specific microRNA (miR)137 and 501-3p, which target GluA1 AMPA subunit, in the developing hippocampus in vitro. Here, we explored how PAE mice may alter AMPAergic synapses in the hippocampus, and its effects on behavior. MethodsTo model PAE, we exposed C57Bl/6 pregnant mice to 10 % EtOH during during the first 10 days of gestation (GD 0–10; equivalent to the first trimester of pregnancy in humans). AMPA subunits postsynaptic expression in the hippocampus, electrical properties of CA1 neurons, memory recognition, and locomotor functions were then analyzed in adolescent PAE-exposed offspring. ResultsPAE adolescent mice showed dysregulation of AMPAergic neurotransmission, and increased miR 501-3p expression, associated with a significant reduction of spontaneous AMPA currents and intrinsic somatic excitability. In addition, PAE reduced the phosphorylation of AMPAR-containing GluA1 subunit, despite an increase in its total levels. Of note, the total levels of GluA2 and GluA3 AMPA receptors were enhanced as well. Consistently, at behavioral level, PAE reduced object recognition without altering locomotor activity. ConclusionsOur study shows that PAE leads to dysfunctional formation of AMPAergic synapses that could be responsible for neurobehavioral impairments, contributing to the understanding of the pathogenesis of FASD.

Inhibiting AMPA receptor signaling in oligodendrocytes rescues synapse loss in a model of autoimmune demyelination

Inhibiting AMPA receptor signaling in oligodendrocytes rescues synapse loss in a model of autoimmune demyelination

In-Situ Structure and Topography of AMPA Receptor Scaffolding Complexes Visualized by CryoET.

Most synapses in the brain transmit information by the presynaptic release of vesicular glutamate, driving postsynaptic depolarization through AMPA-type glutamate receptors (AMPARs). The nanometer-scale topography of synaptic AMPARs regulates response amplitude by controlling the number of receptors activated by synaptic vesicle fusion. The mechanisms controlling AMPAR topography and their interactions with postsynaptic scaffolding proteins are unclear, as is the spatial relationship between AMPARs and synaptic vesicles. Here, we used cryo-electron tomography to map the molecular topography of AMPARs and visualize their in-situ structure. Clustered AMPARs form structured complexes with postsynaptic scaffolding proteins resolved by sub-tomogram averaging. Sub-synaptic topography mapping reveals the presence of AMPAR nanoclusters with exclusion zones beneath synaptic vesicles. Our molecular-resolution maps visualize the predominant information transfer path in the nervous system.

Effectiveness and safety of Perampanel in refractory status epilepticus: a case series.

Perampanel is a selective non-competitive antagonist of AMPA receptors, and the first agent of this class to become available for the treatment of epilepsy. It could be a useful tool for treatment of refractory status epilepticus (RSE). We describe a series of eight RSE cases treated with Perampanel. Perampanel was successful in terminating SE in all the described cases. Only in one patient a severe psychomotor agitation occurred, but without needing PER discontinuation. No other adverse events were observed. Our case series of eight patients, albeit small, broadens the clinical experiences on the efficacy and safety of PER as a treatment for RSE. It may also support the early use of PER, considering the role of AMPA receptors in sustaining epileptic firing in SE. Further studies are warranted to clarify the potential of Perampanel in the treatment of status epilepticus and, in particular, in RSE.

Expression and role of CNIH2 in prostate cancer.

Prostate cancer is one of the most common cancers in men and poses a significant threat to global male health. Traditional prostate cancer assessment methods have certain limitations, necessitating the identification of new prognostic factors and treatment targets. Our study revealed that low expression of the cornichon family AMPA receptor auxiliary protein 2 (CNIH2) gene was associated with a better progression-free survival rate in prostate cancer patients. The area under the receiver operating characteristic (ROC) curve (AUC) showed that the prognostic ability of the CNIH2 gene was high at 1, 3, and 5 years. The gene was an independent prognostic factor according to multivariate analysis. Functional verification experiments showed that knocking down the CNIH2 gene could inhibit the proliferation, migration and invasion of prostate cancer cells and could also inhibit tumor growth in nude mice. Our study is the first to reveal the important role of the CNIH2 gene in prostate cancer. This discovery provides a new research direction for individualized treatment and prognostic evaluation of prostate cancer.

Hippocampal Nogo66-NgR1 signaling activation restricts postsynaptic assembly in aged mice with postoperative neurocognitive disorders.

Postoperative neurocognitive disorders (pNCD) are a common neurological complication, especially in elderly following anesthesia and surgery. Yet, the underlying mechanisms of pNCD remain elusive. This study aimed to investigate the molecular mechanisms that compromise synaptic metaplasticity in pNCD development with a focus on the involvement of Nogo-66 receptor 1 (NgR1) in the pathogenesis of pNCD in aged mice. Aged mice subjected to anesthesia and laparotomy surgery exhibited anxiety-like behavior and contextual fear memory impairment. Moreover, the procedure significantly increased NogoA and NgR1 expressions, particularly in the hippocampal CA1 and CA3 regions. This increase led to the depolymerization of F-actin, attributed to the activation of the RhoA-GTPase, resulting in a reduction of dendritic spines and changes in their morphology. Additionally, these changes hindered the efficient postsynaptic delivery of the subunit GluA1 and GluA2 of AMPA receptors (AMPARs), consequently diminishing excitatory neurotransmission in the hippocampus. Importantly, administering the competitive NgR1 antagonist peptide NEP1-40 (Nogo-A extracellular peptide residues 1-40 amino acids of Nogo-66) and Fasudil (a Rho-kinase inhibitor) effectively mitigated synaptic impairments and reversed neurocognitive deficits in aged mice following anesthesia and surgery. Our work indicates that high hippocampal Nogo66-NgR1 signaling disrupts postsynaptic AMPA receptor surface delivery due to F-actin depolymerization in the pathophysiology of pNCD.

Characterization of patients with major psychiatric disorders with AMPA receptor positron emission tomography.

Synaptic phenotypes in living patients with psychiatric disorders are poorly characterized. Excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a fundamental component for neurotransmission. We recently developed a positron emission tomography (PET) tracer for AMPAR, [11C]K-2, the first technology to visualize and quantify AMPARs density in living human brain. In this study, we characterized patients with major psychiatric disorders with [11C]K-2. One hundred forty-nine patients with psychiatric disorders (schizophrenia, n = 42; bipolar disorder, n = 37; depression, n = 35; and autism spectrum disorder, n = 35) and 70 healthy participants underwent a PET scan with [11C]K-2 for measurement of AMPAR density. We detected brain regions that showed correlation between AMPAR density and symptomatology scores in each of four disorders. We also found brain areas with significant differences in AMPAR density between patients with each psychiatric disorder and healthy participants. Some of these areas were observed across diseases, indicating that these are commonly affected areas throughout psychiatric disorders. Schizophrenia, bipolar disorder, depression, and autism spectrum disorder are uniquely characterized by AMPAR distribution patterns. Our approach to psychiatric disorders using [11C]K-2 can elucidate the biological mechanisms across diseases and pave the way to develop novel diagnostics and therapeutics based on the synapse physiology.

Assessment of neuromodulatory effects of Origanum punonense danin essential oil on AMPA receptor function using whole-cell patch-clamp technique

Introduction: The quest for natural compounds with neuromodulatory properties has gained significant momentum in neuropharmacology. Among these, Origanum punonense (O. punonense) essential oil (EO) stands out due to its rich bioactive profile, particularly characterized by carvacrol. This study aimed to elucidate the effects of O. punonense EO on α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), crucial synaptic plasticity, and cognitive function mediators. Methods: Leaves of O. punonense were collected along the Dead Sea coast in Jericho. After washing, it was dried in the shade for 15 days and ground. Essential oil was extracted using a microwave-ultrasonic method, with ultrasonic waves to enhance extraction. Using whole-cell patch-clamp techniques, we studied the effects of O. punonense EO on AMPAR kinetics in HEK293t cells transfected with homomeric and heteromeric subunits. Results: O. punonense EO significantly reduced AMPAR's whole-cell currents, indicating a targeted modulation of synaptic responses. Oil administration inhibited the currents for glutamate receptor subunits GluA1 (reduced from 885±58 pA to 342±20 pA), GluA1/2 (from 627±77 pA to 209±36 pA), GluA2 (from 1125±112 pA to 256±37 pA), and GluA2/3 (from 474±79 pA to 125±31 pA). The EO decreased the desensitization rate significantly for GluA2 and GluA2/3 (p < 0.01) and for GluA1/2 (p < 0.05), except for GluA1. In addition, the EO increased the deactivation rate significantly for GluA2 and GluA2/3 (p < 0.01) and for GluA1/2 (p < 0.05), with no effect observed on GluA1. Conclusions: This study highlights the possible properties of O. punonense EO and suggests future research to understand its medicinal benefits in neurodegenerative diseases.

The effect of Amantadine on recovery, postoperative cognitive dysfunction and pain after propofol anesthesia in mice

IntroductionPostoperative cognitive dysfunction (POCD) encompasses a spectrum of cognitive impairments following surgery, attributed to disruptions in brain homeostasis. The pathogenesis involves glutamate toxicity, GABA receptor dysfunction, and alterations in NMDA and AMPA receptors. This study aimed to investigate the impact of pre-anesthetic amantadine administration on postoperative recovery time, POCD, and stress-related pain levels when combined with propofol anesthesia. MethodsTwenty-four adult male BALB/C mice were divided into four groups: Control, Propofol, Amantadine, and Amantadine+Propofol. Amantadine and propofol doses were administered intraperitoneally based on previous literature. Recovery time, pain levels (assessed via tail pinch and hot plate tests), cognitive functions (evaluated through Morris Water Maze), and locomotor activity (measured via Open Field Test) were recorded. ResultsAmantadine administration significantly reduced recovery time from propofol anesthesia, prolonged pain perception, and preserved cognitive functions compared to propofol alone. The time spent in the target quadrant in the Morris Water Maze was significantly longer in groups receiving amantadine. Additionally, the distance covered until finding the platform was significantly shorter in the propofol-only group. DiscussionAmantadine's neuroprotective effects, attributed to its antagonistic action on glutamate and NMDA receptors, mitigate the detrimental effects of propofol on cognitive function and pain perception. This study highlights the potential of combining amantadine with propofol to enhance postoperative outcomes. ConclusionAmantadine administration before propofol anesthesia positively influenced postoperative recovery, cognitive function preservation, and stress-related pain perception in mice. These findings suggest a potential therapeutic strategy to mitigate POCD and pain associated with surgery.

Exploring the role of AMPA receptor auxiliary proteins in synaptic functions and diseases.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptors (AMPARs) mediate rapid excitatory synaptic transmission in the mammalian brain, primarily driven by the neurotransmitter glutamate. The modulation of AMPAR activity, particularly calcium-permeable AMPARs (CP-AMPARs), is crucially influenced by various auxiliary subunits. These subunits are integral membrane proteins that bind to the receptor's core and modify its functional properties, including ion channel kinetics and receptor trafficking. This review comprehensively catalogs all known AMPAR auxiliary proteins, providing vital insights into the biochemical mechanisms governing synaptic modulation and the specific impact of CP-AMPARs compared to their calcium-impermeable AMPA receptor (CI-AMPARs). Understanding the complex interplay between AMPARs and their auxiliary subunits in different brain regions is essential for elucidating their roles in cognitive functions such as learning and memory. Importantly, alterations in these auxiliary proteins' expression, function or interactions have been implicated in various neurological disorders. Aberrant signaling through CP-AMPARs, in particular, is associated with severe synaptic dysfunctions across neurodevelopmental, neurodegenerative and psychiatric conditions. Targeting the distinct properties of AMPAR-auxiliary subunit complexes, especially those involving CP-AMPARs, could disclose new therapeutic strategies, potentially allowing for more precise interventions in treating complex neuronal disorders.

LRRTM2 controls presynapse nano-organization and AMPA receptor sub-positioning through Neurexin-binding interface

Synapses are organized into nanocolumns that control synaptic transmission efficacy through precise alignment of postsynaptic neurotransmitter receptors and presynaptic release sites. Recent evidence show that Leucine-Rich Repeat Transmembrane protein LRRTM2, highly enriched and confined at synapses, interacts with Neurexins through its C-terminal cap, but the role of this binding interface has not been explored in synapse formation and function. Here, we develop a conditional knock-out mouse model (cKO) to address the molecular mechanisms of LRRTM2 regulation, and its role in synapse organization and function. We show that LRRTM2 cKO specifically impairs excitatory synapse formation and function in mice. Surface expression, synaptic clustering, and membrane dynamics of LRRTM2 are tightly controlled by selective motifs in the C-terminal domain. Conversely, the N-terminal domain controls presynapse nano-organization and postsynapse AMPAR sub-positioning and stabilization through the recently identified Neurexin-binding interface. Thus, we identify LRRTM2 as a central organizer of pre- and post- excitatory synapse nanostructure through interaction with presynaptic Neurexins.

Роль ванілоїдного рецептора типу 1 та глутаматних рецепторів у синаптичній активності нейронів пластинки X спинного мозку щурів

This study is aimed at understanding the mechanisms of nociceptive signaling in lamina X of the spinal cord, which are involved in the regulation of pain sensations. First, tetrodotoxin, which blocks action potentials, was applied to the system, which made it possible to isolate miniature synaptic activity (mEPSCs). After that, they added pidal, an agonist of TRPV1 receptors, which caused a significant increase in the frequency and amplitude of mEPSCs. Against the background of tetrodotoxin, the effect of capsaicin was biphasic: at first, the frequency of events increased sharply, after which it gradually decreased, but the amplitude increased. A control, without tetrodotoxin, application of capsaicin also caused an increase in synaptic activity, but this effect was not biphasic. Additional blockade of NMDA receptors (AP-5) partially reduced capsaicin-induced activity, while an AMPA receptor blocker (CNQX) almost completely abolished it, suggesting a critical role of glutamate receptors in maintaining this activity. The obtained results emphasize the importance of TRPV1 receptors in central sensitization and the possibility of its regulation, which opens new ways of modulation of chronic pain.

The diversity of AMPA receptor inhibition mechanisms among amidine-containing compounds.

Amidine-containing compounds are primarily known as antiprotozoal agents (pentamidine, diminazene, furamidine) or as serine protease inhibitors (nafamostat, sepimostat, camostat, gabexate). DAPI is widely recognized as a fluorescent DNA stain. Recently, it has been shown that these compounds also act as NMDA receptor inhibitors. In this study, we examined the activity of these compounds and analyzed the mechanisms of action in relation to another important class of ionotropic glutamate receptors-calcium-permeable AMPA receptors (CP-AMPARs) and calcium-impermeable AMPA receptors (CI-AMPARs) - using the whole-cell patch-clamp method on isolated male Wistar rat brain neurons. Gabexate and camostat were found to be inactive. Other compounds preferentially inhibited calcium-permeable AMPA receptors with IC50 values of 30-60µM. DAPI and furamidine were also active against CI-AMPARs with IC50s of 50-60μM, while others showed poor activity. All active compounds acted as channel blockers, which are able for permeating into the cytoplasm on both CP- and CI-AMPARs. Specifically, sepimostat showed trapping in the closed CP-AMPAR channel. Furamidine and DAPI demonstrated a voltage-independent action on CI-AMPARs, indicating binding to an additional superficial site. While the majority of compounds inhibited glutamate-activated steady-state currents as well as kainate-activated currents on CI-AMPARs, pentamidine significantly potentiated glutamate-induced steady-state responses. The potentiating effect of pentamidine resembles the action of the positive allosteric modulator cyclothiazide although the exact binding site remains unclear. Thus, this study, together with our previous research on NMDA receptors, provides a comprehensive overview of this novel group of ionotropic glutamate receptors inhibitors with a complex pharmacological profile, remarkable diversity of effects and mechanisms of action.

AMPA Receptor Encephalitis: A Decade Long Unveiling of Clinical, Radiographic and Serological Findings in an Untreated Patient

AMPA Receptor Encephalitis: A Decade Long Unveiling of Clinical, Radiographic and Serological Findings in an Untreated Patient

A circuit from lateral hypothalamic to dorsal hippocampal dentate gyrus modulates behavioral despair in mice.

Behavioral despair is one of the clinical manifestations of major depressive disorder and an important cause of disability and death. However, the neural circuit mechanisms underlying behavioral despair are poorly understood. In a well-established chronic behavioral despair (CBD) mouse model, using a combination of viral tracing, in vivo fiber photometry, chemogenetic and optogenetic manipulations, in vitro electrophysiology, pharmacological profiling techniques, and behavioral tests, we investigated the neural circuit mechanisms in regulating behavioral despair. Here, we found that CBD enhanced CaMKIIα neuronal excitability in the dorsal dentate gyrus (dDG) and dDGCaMKIIα neurons involved in regulating behavioral despair in CBD mice. Besides, dDGCaMKIIα neurons received 5-HT inputs from median raphe nucleus (MRN) and were mediated by 5-HT1A receptors, whereas MRN5-HT neurons received CaMKIIα inputs from lateral hypothalamic (LH) and were mediated by AMPA receptors to regulate behavioral despair. Furthermore, fluvoxamine exerted its role in resisting behavioral despair through the LH-MRN-dDG circuit. These findings suggest that a previously unidentified circuit of LHCaMKIIα-MRN5-HT-dDGCaMKIIα mediates behavioral despair induced by CBD. Furthermore, these support the important role of AMPA receptors in MRN and 5-HT1A receptors in dDG that might be the potential targets for treatment of behavioral despair, and explain the neural circuit mechanism of fluvoxamine-resistant behavioral despair.

Calcium-permeable AMPA receptors govern PV neuron feature selectivity

The brain helps us survive by forming internal representations of the external world1,2. Excitatory cortical neurons are often precisely tuned to specific external stimuli3,4. However, inhibitory neurons, such as parvalbumin-positive (PV) interneurons, are generally less selective5. PV interneurons differ from excitatory neurons in their neurotransmitter receptor subtypes, including AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs)6,7. Excitatory neurons express calcium-impermeable AMPARs that contain the GluA2 subunit (encoded by GRIA2), whereas PV interneurons express receptors that lack the GluA2 subunit and are calcium-permeable (CP-AMPARs). Here we demonstrate a causal relationship between CP-AMPAR expression and the low feature selectivity of PV interneurons. We find low expression stoichiometry of GRIA2 mRNA relative to other subunits in PV interneurons that is conserved across ferrets, rodents, marmosets and humans, and causes abundant CP-AMPAR expression. Replacing CP-AMPARs in PV interneurons with calcium-impermeable AMPARs increased their orientation selectivity in the visual cortex. Manipulations to induce sparse CP-AMPAR expression demonstrated that this increase was cell-autonomous and could occur with changes beyond development. Notably, excitatory–PV interneuron connectivity rates and unitary synaptic strength were unaltered by CP-AMPAR removal, which suggested that the selectivity of PV interneurons can be altered without markedly changing connectivity. In Gria2-knockout mice, in which all AMPARs are calcium-permeable, excitatory neurons showed significantly degraded orientation selectivity, which suggested that CP-AMPARs are sufficient to drive lower selectivity regardless of cell type. Moreover, hippocampal PV interneurons, which usually exhibit low spatial tuning, became more spatially selective after removing CP-AMPARs, which indicated that CP-AMPARs suppress the feature selectivity of PV interneurons independent of modality. These results reveal a new role of CP-AMPARs in maintaining low-selectivity sensory representation in PV interneurons and implicate a conserved molecular mechanism that distinguishes this cell type in the neocortex.