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Extrasynaptic NMDA Receptors Bidirectionally Modulate Intrinsic Excitability of Inhibitory Neurons. 2022

Lulu Yao, and Yi Rong, and Xiaoyan Ma, and Haifu Li, and Di Deng, and Yongjun Chen, and Sungchil Yang, and Tao Peng, and Tao Ye, and Feixue Liang, and Nenggui Xu, and Qiang Zhou
South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, P. R. China.

The NMDA subtype glutamate receptors (NMDARs) play important roles in both physiological and pathologic processes in the brain. Compared with their critical roles in synaptic modifications and excitotoxicity in excitatory neurons, much less is understood about the functional contributions of NMDARs to the inhibitory GABAergic neurons. By using selective NMDAR inhibitors and potentiators, we here show that NMDARs bidirectionally modulate the intrinsic excitability (defined as spontaneous/evoked spiking activity and EPSP-spike coupling) in inhibitory GABAergic neurons in adult male and female mice. This modulation depends on GluN2C/2D- but not GluN2A/2B-containing NMDARs. We further show that NMDAR modulator EU1794-4 mostly enhances extrasynaptic NMDAR activity, and by using it we demonstrate a significant contribution of extrasynaptic NMDARs to the modulation of intrinsic excitability in inhibitory neurons. Together, this bidirectional modulation of intrinsic excitability reveals a previously less appreciated importance of NMDARs in the second-to-second functioning of inhibitory GABAergic neurons.SIGNIFICANCE STATEMENT NMDA subtype of glutamate receptors (NMDARs) have important roles in brain functions, including both physiological and pathologic ones. The role of NMDARs in inhibitory neurons has been less elucidated compared with that in excitatory neurons. Our results demonstrate the importance of GluN2C/GluN2D-containing but not GluN2A/GluN2B-containing extrasynaptic NMDARs in modulating the intrinsic excitability of inhibitory neurons. These results further suggest distinct contributions of subsynaptic locations and subunit compositions of NMDARs to their functions in excitatory and inhibitory neurons. The above findings have implications for better understanding of brain diseases, such as schizophrenia.

UI MeSH Term Description Entries
D008297 Male Males
D005260 Female Females
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013569 Synapses Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate via direct electrical coupling with ELECTRICAL SYNAPSES. Several other non-synaptic chemical or electric signal transmitting processes occur via extracellular mediated interactions. Synapse
D016194 Receptors, N-Methyl-D-Aspartate A class of ionotropic glutamate receptors characterized by affinity for N-methyl-D-aspartate. NMDA receptors have an allosteric binding site for glycine which must be occupied for the channel to open efficiently and a site within the channel itself to which magnesium ions bind in a voltage-dependent manner. The positive voltage dependence of channel conductance and the high permeability of the conducting channel to calcium ions (as well as to monovalent cations) are important in excitotoxicity and neuronal plasticity. N-Methyl-D-Aspartate Receptor,N-Methyl-D-Aspartate Receptors,NMDA Receptor,NMDA Receptor-Ionophore Complex,NMDA Receptors,Receptors, NMDA,N-Methylaspartate Receptors,Receptors, N-Methylaspartate,N Methyl D Aspartate Receptor,N Methyl D Aspartate Receptors,N Methylaspartate Receptors,NMDA Receptor Ionophore Complex,Receptor, N-Methyl-D-Aspartate,Receptor, NMDA,Receptors, N Methyl D Aspartate,Receptors, N Methylaspartate
D016202 N-Methylaspartate An amino acid that, as the D-isomer, is the defining agonist for the NMDA receptor subtype of glutamate receptors (RECEPTORS, NMDA). N-Methyl-D-aspartate,NMDA,N-Methyl-D-aspartic Acid,Acid, N-Methyl-D-aspartic,N Methyl D aspartate,N Methyl D aspartic Acid,N Methylaspartate
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D059330 GABAergic Neurons Neurons whose primary neurotransmitter is GAMMA-AMINOBUTYRIC ACID. GABA Cells,GABA Neurons,Cell, GABA,Cells, GABA,GABA Cell,GABA Neuron,GABAergic Neuron,Neuron, GABA,Neuron, GABAergic,Neurons, GABA,Neurons, GABAergic
D018698 Glutamic Acid A non-essential amino acid naturally occurring in the L-form. Glutamic acid is the most common excitatory neurotransmitter in the CENTRAL NERVOUS SYSTEM. Aluminum L-Glutamate,Glutamate,Potassium Glutamate,D-Glutamate,Glutamic Acid, (D)-Isomer,L-Glutamate,L-Glutamic Acid,Aluminum L Glutamate,D Glutamate,Glutamate, Potassium,L Glutamate,L Glutamic Acid,L-Glutamate, Aluminum

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