scholarly journals Deficiency of the CYLD Impairs Fear Memory of Mice and Disrupts Neuronal Activity and Synaptic Transmission in the Basolateral Amygdala

2021 ◽  
Vol 15 ◽  
Author(s):  
Hui-dong Li ◽  
Dan-ni Li ◽  
Li Yang ◽  
Cheng Long
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Activity ◽  
Basolateral Amygdala ◽  
Fear Memory ◽  
Brain Regions ◽  
Fear Learning ◽  
Neuronal Activation ◽  
Excitatory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Animal Survival

Fear learning and memory are crucial for animal survival. Abnormal fear memory is a hallmark of many neuropsychiatric disorders. Appropriate neuronal activation and excitability in the basolateral amygdala (BLA) are necessary for the formation of fear memory. The gene cylindromatosis (Cyld), which encodes a lysine-63 deubiquitinase, is expressed in several brain regions including the amygdala. The functions of the cylindromatosis protein (CYLD) in the regulation of the neuronal activity, neural circuits and fear memory, remain largely unknown, however. Here, we report that Cyld knockout impairs amygdala-dependent tone-cued fear memory. The number of c-Fos+ neurons responding to the tone-cued fear test was reduced in the BLA of Cyld–/– mice, suggesting that the absence of CYLD causes aberrant neuronal activation. We found that this aberrant neuronal activation in the BLA of Cyld–/– mice may relate to the decreased excitability of principal neurons. Another possibility of aberrant neuronal activation could be the impaired excitatory synaptic transmission in the BLA of Cyld–/– mice. Specifically, both the frequency of spontaneous excitatory postsynaptic currents and the amplitude of miniature excitatory postsynaptic currents in BLA principal neurons were decreased. In addition, Cyld mutation caused an increase in both the frequency of miniature inhibitory postsynaptic currents in principal neurons and the number of parvalbumin+ interneurons, consistent with excessive local circuit inhibition in the BLA of Cyld–/– mice. Taken together, these results suggest that CYLD deficiency disrupts the neuronal activity and synaptic transmission in the BLA of mice which may contribute to the impaired fear memory observed in Cyld–/– mice.

Development of Excitatory Circuitry in the Hippocampus

1998 ◽  
Vol 79 (4) ◽  
pp. 2013-2024 ◽  
Author(s):  
Albert Y. Hsia ◽  
Robert C. Malenka ◽  
Roger A. Nicoll
Keyword(s):  
Synaptic Transmission ◽  
Action Potentials ◽  
Pyramidal Cells ◽  
Excitatory Synaptic Transmission ◽  
Developmental Strategy ◽  
Excitatory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Quantal Size ◽  
Physiological Approach ◽  
Local Circuitry

Hsia, Albert Y., Robert C. Malenka, and Roger A. Nicoll. Development of excitatory circuitry in the hippocampus. J. Neurophysiol. 79: 2013–2024, 1998. Assessing the development of local circuitry in the hippocampus has relied primarily on anatomic studies. Here we take a physiological approach, to directly evaluate the means by which the mature state of connectivity between CA3 and CA1 hippocampal pyramidal cells is established. Using a technique of comparing miniature excitatory postsynaptic currents (mEPSCs) to EPSCs in response to spontaneously occurring action potentials in CA3 cells, we found that from neonatal to adult ages, functional synapses are created and serve to increase the degree of connectivity between CA3-CA1 cell pairs. Neither the probability of release nor mean quantal size was found to change significantly with age. However, the variability of quantal events decreases substantially as synapses mature. Thus in the hippocampus the developmental strategy for enhancing excitatory synaptic transmission does not appear to involve an increase in the efficacy at individual synapses, but rather an increase in the connectivity between cell pairs.

scholarly journals Influences of Morphine on the Spontaneous and Evoked Excitatory Postsynaptic Currents in Lateral Amygdala of Rats

2016 ◽  
pp. 165-169 ◽  
Author(s):  
J.-J. ZHANG ◽  
X.-D. LIU ◽  
L.-C. YU
Keyword(s):  
Synaptic Transmission ◽  
Excitatory Synaptic Transmission ◽  
Morphine Treatment ◽  
Lateral Amygdala ◽  
Excitatory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Whole Cell Patch Clamp ◽  
The Central Nervous System ◽  
Underlying Mechanisms

Acute morphine exposure induces antinociceptive activity, but the underlying mechanisms in the central nervous system are unclear. Using whole-cell patch clamp recordings, we explore the role of morphine in the modulation of excitatory synaptic transmission in lateral amygdala neurons of rats. The results demonstrate that perfusion of 10 μM of morphine to the lateral amygdala inhibits the discharge frequency significantly. We further find that there are no significant influences of morphine on the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Interestingly, morphine shows no marked influence on the evoked excitatory postsynaptic currents (eEPSCs) in the lateral amygdala neurons. These results indicate that acute morphine treatment plays an important role in the modulation on the excitatory synaptic transmission in lateral amygdala neurons of rats.

scholarly journals Homeostatic Plasticity Hypothesis and Mechanisms of Neocortical Epilepsies

2005 ◽  
Vol 5 (4) ◽  
pp. 133-135 ◽  
Author(s):  
Jaideep Kapur ◽  
Stacey Trotter
Keyword(s):  
Synaptic Plasticity ◽  
Neuronal Activity ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Homeostatic Plasticity ◽  
Excitatory Synapses ◽  
Excitatory Postsynaptic Currents ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Homeostatic Synaptic Plasticity

Homeostatic Synaptic Plasticity Can Explain Posttraumatic Epileptogenesis in Chronically Isolated Neocortex Houweling AR, Bazhenov M, Timofeev I, Steriade M, Sejnowski TJ Cereb Cortex 2004 [Epub ahead of print] Permanently isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of posttraumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in permanently isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis, we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in permanently isolated neocortex. These burst discharges lasted a few hundred milliseconds, propagated at 1 to 3 cm/s and consisted of large (10–15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of posttraumatic epileptogenesis. Excitatory and Inhibitory Postsynaptic Currents in a Rat Model of Epileptogenic Microgyria Jacobs KM, Prince DA J Neurophysiol 2005;93:687–696 Developmental cortical malformations are common in patients with intractable epilepsy; however, mechanisms contributing to this epileptogenesis are currently poorly understood. We previously characterized hyperexcitability in a rat model that mimics the histopathology of human four-layered microgyria. Here we examined inhibitory and excitatory postsynaptic currents in this model to identify functional alterations that might contribute to epileptogenesis associated with microgyria. We recorded isolated whole-cell excitatory postsynaptic currents and GABAA receptor–mediated inhibitory currents from layer V pyramidal neurons in the region previously shown to be epileptogenic (paramicrogyral area) and in homotopic control cortex. Epileptiform-like activity could be evoked in 60% of paramicrogyral (PMG) cells by local stimulation. The peak conductance of both spontaneous and evoked inhibitory postsynaptic currents was significantly larger in all PMG cells compared with controls. This difference in amplitude was not present after blockade of ionotropic glutamatergic currents or for miniature (m) inhibitory postsynaptic currents, suggesting that it was due to the excitatory afferent activity driving inhibitory neurons. This conclusion was supported by the finding that glutamatereceptor antagonist application resulted in a significantly greater reduction in spontaneous inhibitory postsynaptic current frequency in one PMG cell group (PMGE) compared with control cells. The frequency of both spontaneous and miniature excitatory postsynaptic currents was significantly greater in all PMG cells, suggesting that pyramidal neurons adjacent to a microgyrus receive more excitatory input than do those in control cortex. These findings suggest that there is an increase in numbers of functional excitatory synapses on both interneurons and pyramidal cells in the PMG cortex, perhaps due to hyperinnervation by cortical afferents originally destined for the microgyrus proper.

scholarly journals Fear Memory

2016 ◽  
Vol 96 (2) ◽  
pp. 695-750 ◽  
Author(s):  
Ivan Izquierdo ◽  
Cristiane R. G. Furini ◽  
Jociane C. Myskiw
Keyword(s):  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Inhibitory Avoidance ◽  
Long Term Potentiation ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Fear Learning ◽  
Term Potentiation ◽  
Mechanisms Of Memory

Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general.

scholarly journals microRNA mir-598-3p mediates susceptibility to stress-enhancement of remote fear memory

2019 ◽  
Author(s):  
Meghan E Jones ◽  
Stephanie E. Sillivan ◽  
Sarah Jamieson ◽  
Gavin Rumbaugh ◽  
Courtney A. Miller
Keyword(s):  
Basolateral Amygdala ◽  
Differential Susceptibility ◽  
Anxiolytic Effect ◽  
Bioinformatic Analysis ◽  
Fear Memory ◽  
Fear Learning ◽  
Small Rna Sequencing ◽  
Female Mice ◽  
The Impact

ABSTRACTmicroRNAs (miRNAs) have emerged as potent regulators of learning, recent memory and extinction. However, our understanding of miRNAs directly involved in regulating complex psychiatric conditions perpetuated by aberrant memory, such as in posttraumatic stress disorder (PTSD), remains limited. To begin to address the role of miRNAs in persistent memory, we performed small-RNA sequencing on basolateral amygdala (BLA) tissue to identify miRNAs altered by auditory fear conditioning (FC) one month after training. mir-598-3p, a highly conserved miRNA previously unstudied in the brain, was downregulated in the BLA. Further decreasing BLA mir-598-3p levels did not alter the expression or extinction of the remote fear memory. Given that stress is a critical component in PTSD, we next assessed the impact of stress-enhanced fear learning (SEFL) on mir-598-3p levels, finding the miRNA is elevated in the BLA of male, but not female, mice susceptible to the effects of stress in SEFL. Accordingly, intra-BLA inhibition of mir-598-3p interfered with expression and extinction of the remote fear memory in male, but not female, mice. This effect could not be attributed to an anxiolytic effect of miRNA inhibition. Finally, bioinformatic analysis following quantitative proteomics on BLA tissue collected 30 days post-SEFL training identified putative mir-598-3p targets and related pathways mediating the differential susceptibility, with evidence for regulation of the actin cytoskeleton.

scholarly journals TRPV1 channels contribute to spontaneous glutamate release in nucleus tractus solitarii following chronic intermittent hypoxia

2019 ◽  
Vol 121 (3) ◽  
pp. 881-892 ◽  
Author(s):  
David D. Kline ◽  
Sheng Wang ◽  
Diana L. Kunze
Keyword(s):  
Synaptic Transmission ◽  
Intermittent Hypoxia ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Nucleus Tractus Solitarii ◽  
Chronic Intermittent Hypoxia ◽  
Excitatory Postsynaptic Currents ◽  
Epsc Amplitude ◽  
Postsynaptic Currents ◽  
Transient Receptor

Chronic intermittent hypoxia (CIH) reduces afferent-evoked excitatory postsynaptic currents (EPSCs) but enhances basal spontaneous (s) and asynchronous (a) EPSCs in second-order neurons of nucleus tractus solitarii (nTS), a major area for cardiorespiratory control. The net result is an increase in synaptic transmission. The mechanisms by which this occurs are unknown. The N-type calcium channel and transient receptor potential cation channel TRPV1 play prominent roles in nTS sEPSCs and aEPSCs. The functional role of these channels in CIH-mediated afferent-evoked EPSC, sEPSC, and aEPSC was tested in rat nTS slices following antagonist inhibition and in mouse nTS slices that lack TRPV1. Block of N-type channels decreased aEPSCs in normoxic and, to a lesser extent, CIH-exposed rats. sEPSCs examined in the presence of TTX (miniature EPSCs) were also decreased by N-type block in normoxic but not CIH-exposed rats. Antagonist inhibition of TRPV1 reduced the normoxic and the CIH-mediated increase in sEPSCs, aEPSCs, and mEPSCs. As in rats, in TRPV1+/+ control mice, aEPSCs, sEPSCs, and mEPSCs were enhanced following CIH. However, none were enhanced in TRPV1−/− null mice. Normoxic tractus solitarii (TS)-evoked EPSC amplitude, and the decrease after CIH, were comparable in control and null mice. In rats, TRPV1 was localized in the nodose-petrosal ganglia (NPG) and their central branches. CIH did not alter TRPV1 mRNA but increased its protein in NPG consistent with an increased contribution of TRPV1. Together, our studies indicate TRPV1 contributes to the CIH increase in aEPSCs and mEPSCs, but the CIH reduction in TS-EPSC amplitude occurs via an alternative mechanism. NEW & NOTEWORTHY This study provides information on the underlying mechanisms responsible for the chronic intermittent hypoxia (CIH) increase in synaptic transmission that leads to exaggerated sympathetic nervous and respiratory activity at baseline and in response to low oxygen. We demonstrate that the CIH increase in asynchronous and spontaneous excitatory postsynaptic currents (EPSCs) and miniature EPSCs, but not decrease in afferent-driven EPSCs, is dependent on transient receptor potential vanilloid type 1 (TRPV1). Thus TRPV1 is important in controlling nucleus tractus solitarii synaptic activity during CIH.

scholarly journals Effect of Xenon on Excitatory and Inhibitory Transmission in Rat Spinal Ventral Horn Neurons

2012 ◽  
Vol 116 (5) ◽  
pp. 1025-1034 ◽  
Author(s):  
Tomohiro Yamamoto ◽  
Hiroyuki Honda ◽  
Hiroshi Baba ◽  
Tatsuro Kohno
Keyword(s):  
Synaptic Transmission ◽  
Propionic Acid ◽  
Minimum Alveolar Concentration ◽  
Ventral Horn ◽  
Excitatory Postsynaptic Currents ◽  
Inhibitory Synaptic Transmission ◽  
Postsynaptic Currents ◽  
Aspartate Receptor ◽  
Induced Currents ◽  
Spinal Lamina

Background The minimum alveolar concentration is determined in the spinal cord rather than in the brain. Xenon inhibits glutamatergic excitatory synaptic transmission in the dorsal horn neurons. However, its actions in the ventral horn neurons have not been investigated. Methods The effects of 50 or 75% xenon on excitatory and inhibitory synaptic transmission were examined in the spinal lamina IX neurons of neonatal rats by using a whole cell patch clamp technique. Results Fifty percent xenon inhibited the α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid-induced currents (amplitudes = 72 ± 9% and integrated area = 73 ± 13% of the control values), and α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid receptor-mediated electrically evoked excitatory postsynaptic currents (amplitudes = 69 ± 13% of the control values). Seventy-five percent xenon similarly inhibited α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid-induced currents. However, xenon had no effect on the N-methyl-D-aspartate-induced currents or N-methyl-D-aspartate receptor-mediated electrically evoked excitatory postsynaptic currents. Xenon decreased the amplitude, but not the frequency, of miniature excitatory postsynaptic currents. There were no discernible effects on the currents induced by γ-aminobutyric acid or glycine or on miniature inhibitory postsynaptic currents. Conclusions Xenon inhibits α-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid receptor-mediated glutamatergic excitatory transmission in the spinal lamina IX neurons via a postsynaptic mechanism. In contrast, there are no substantial effects on N-methyl-D-aspartate receptor-mediated or inhibitory synaptic transmission. The suppressive effects on excitatory synaptic transmission in the ventral horn neurons partly account for the mechanism behind xenon's ability to produce immobility in response to noxious stimuli and to determine the minimum alveolar concentration.

scholarly journals Altered theta / beta frequency synchrony links abnormal anxiety-related behavior to synaptic inhibition in Neuroligin-2 knockout mice

2019 ◽  
Author(s):  
Hugo Cruces-Solis ◽  
Olga Babaev ◽  
Heba Ali ◽  
Carolina Piletti Chatain ◽  
Vasyl Mykytiuk ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Basolateral Amygdala ◽  
Brain Regions ◽  
Synaptic Inhibition ◽  
Bed Nucleus ◽  
Adhesion Protein ◽  
Inhibitory Synaptic Transmission ◽  
Theta Frequency ◽  
Beta Frequency

AbstractInhibitory synaptic transmission plays a key role in the circuits underlying anxiety behaviors, but the network mechanisms by which disruptions in synaptic inhibition contribute to pathological anxiety processing remain largely unknown. Here we addressed this question in mice lacking the inhibitory synapse-specific adhesion protein Neuroligin-2 (Nlgn2), which display widespread reduction in inhibitory synaptic transmission as well as a pronounced anxiety phenotype. To investigate how the lack of synaptic inhibition alters the communication between key brain regions in anxiety processing, we recorded local field potentials (LFPs) simultaneously from a network of brain regions involved in anxiety processing, including the basolateral amygdala (BLA), centromedial amygdala, bed nucleus of the stria terminalis, prefrontal cortex and ventral hippocampus (vHPC). We found that LFP power in the vHPC was profoundly increased while vHPC-directed theta frequency synchrony was disrupted in Nlgn2 KO mice under anxiogenic conditions. Instead, deletion of Nlgn2 increased beta frequency synchrony across the anxiety network, and the theta / beta synchrony ratio strongly predicted anxiety behaviors in an open field paradigm. Local deletion of Nlgn2 in the vHPC and BLA revealed that they encode distinct aspects of the anxiety phenotype of the Nlgn2 KO mice, with vHPC linked to anxiety induced freezing and BLA linked to reduction in exploratory activity. Together, our data demonstrate that alterations in long-range functional connectivity link synaptic inhibition to abnormal anxiety behaviors, and that Nlgn2 KO mice represent an interesting model to study the role of inhibitory synaptic transmission in the circuits underlying anxiety disorders.

scholarly journals Xenon Attenuates Excitatory Synaptic Transmission in the Rodent Prefrontal Cortex and Spinal Cord Dorsal Horn

2009 ◽  
Vol 111 (6) ◽  
pp. 1297-1307 ◽  
Author(s):  
Rainer Haseneder ◽  
Stephan Kratzer ◽  
Eberhard Kochs ◽  
Corinna Mattusch ◽  
Matthias Eder ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Prefrontal Cortex ◽  
Synaptic Transmission ◽  
Ampa Receptor ◽  
Spinal Cord Dorsal Horn ◽  
Substantia Gelatinosa ◽  
Gamma Aminobutyric Acid ◽  
Excitatory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Spinal Cord Dorsal

Background The molecular mechanisms of the inhalational anesthetic xenon are not yet fully understood. Recently, the authors showed that xenon reduces both N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic transmission in a brain slice preparation of the amygdala. In the current study, the authors examined the effects of xenon on synaptic transmission in the prefrontal cortex and the spinal cord dorsal horn (substantia gelatinosa). Methods In rodent brain or spinal cord slice preparations, the authors used patch clamp technique to investigate the impact of xenon on NMDA and AMPA receptor-mediated excitatory postsynaptic currents, as well as on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents. The currents were either evoked upon electrical stimulation (NMDA-eEPSCs and AMPA-eEPSCs) or upon photolysis of caged L-glutamate (p-NMDA-Cs and p-AMPA-Cs). In addition, the authors investigated the effects of xenon on AMPA receptor-mediated miniature excitatory postsynaptic currents. Results In both central nervous system regions, xenon had virtually no effect on inhibitory postsynaptic currents. In the prefrontal cortex (spinal cord), xenon reversibly reduced NMDA-eEPSCs to approximately 58% (72%) and AMPA-eEPSCs to approximately 67% (65%) of control. There was no difference in the xenon-induced reduction of NMDA-eEPSCs and p-NMDA-Cs, or AMPA-eEPSCs and p-AMPA-Cs. Xenon did not affect the frequency of miniature excitatory postsynaptic currents but reduced their amplitude. Conclusions In the current study, the authors found that xenon depresses NMDA and AMPA receptor-mediated synaptic transmission in the prefrontal cortex and the substantia gelatinosa without affecting gamma-aminobutyric acid type A receptor-mediated synaptic transmission. These results provide evidence that the effects of xenon are primarily due to postsynaptic mechanisms.

scholarly journals Modulation of NMDA Receptor Properties and Synaptic Transmission by the NR3A Subunit in Mouse Hippocampal and Cerebrocortical Neurons

2008 ◽  
Vol 99 (1) ◽  
pp. 122-132 ◽  
Author(s):  
Gary Tong ◽  
Hiroto Takahashi ◽  
Shichun Tu ◽  
Yeonsook Shin ◽  
Maria Talantova ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Synaptic Transmission ◽  
Xenopus Oocytes ◽  
Hippocampal Slices ◽  
Excitatory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Mammalian Cell Lines ◽  
Induced Currents ◽  
Channel Properties ◽  
Two Populations

Expression of the NR3A subunit with NR1/NR2 in Xenopus oocytes or mammalian cell lines leads to a reduction in N-methyl-d-aspartate (NMDA)-induced currents and decreased Mg2+ sensitivity and Ca2+ permeability compared with NR1/NR2 receptors. Consistent with these findings, neurons from NR3A knockout (KO) mice exhibit enhanced NMDA-induced currents. Recombinant NR3A can also form excitatory glycine receptors with NR1 in the absence of NR2. However, the effects of NR3A on channel properties in neurons and synaptic transmission have not been fully elucidated. To study physiological roles of NR3A subunits, we generated NR3A transgenic (Tg) mice. Cultured NR3A Tg neurons exhibited two populations of NMDA receptor (NMDAR) channels, reduced Mg2+ sensitivity, and decreased Ca2+ permeability in response to NMDA/glycine, but glycine alone did not elicit excitatory currents. In addition, NMDAR-mediated excitatory postsynaptic currents (EPSCs) in NR3A Tg hippocampal slices showed reduced Mg2+ sensitivity, consistent with the notion that NR3A subunits incorporated into synaptic NMDARs. To study the function of endogenous NR3A subunits, we compared NMDAR-mediated EPSCs in NR3A KO and WT control mice. In NR3A KO mice, the ratio of the amplitudes of the NMDAR-mediated component to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated component of the EPSC was significantly larger than that seen in WT littermates. This result suggests that NR3A subunits contributed to the NMDAR-mediated component of the EPSC in WT mice. Taken together, these results show that NR3A subunits contribute to NMDAR responses from both synaptic and extrasynaptic receptors, likely composed of NR1, NR2, and NR3 subunits.

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