Presynaptic GluN2D receptors detect glutamate spillover and regulate cerebellar GABA release.
Glutamate directly activates N-methyl-d-aspartate (NMDA) receptors on presynaptic inhibitory interneurons and enhances GABA release, altering the excitatory-inhibitory balance within a neuronal circuit. However, which class of NMDA receptors is involved in the detection of glutamate spillover is not known. GluN2D subunit-containing NMDA receptors are ideal candidates as they exhibit a high affinity for glutamate. We now show that cerebellar stellate cells express both GluN2B and GluN2D NMDA receptor subunits. Genetic deletion of GluN2D subunits prevented a physiologically relevant, stimulation-induced, lasting increase in GABA release from stellate cells [long-term potentiation of inhibitory transmission (I-LTP)]. NMDA receptors are tetramers composed of two GluN1 subunits associated to either two identical subunits (di-heteromeric receptors) or to two different subunits (tri-heteromeric receptors). To determine whether tri-heteromeric GluN2B/2D NMDA receptors mediate I-LTP, we tested the prediction that deletion of GluN2D converts tri-heteromeric GluN2B/2D to di-heteromeric GluN2B NMDA receptors. We find that prolonged stimulation rescued I-LTP in GluN2D knockout mice, and this was abolished by GluN2B receptor blockers that failed to prevent I-LTP in wild-type mice. Therefore, NMDA receptors that contain both GluN2D and GluN2B mediate the induction of I-LTP. Because these receptors are not present in the soma and dendrites, presynaptic tri-heteromeric GluN2B/2D NMDA receptors in inhibitory interneurons are likely to mediate the cross talk between excitatory and inhibitory transmission.
Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
Christophe J
CJ
Dubois
Department of Biology, Penn State University, State College, Pennsylvania; and.
Philippe M
PM
Lachamp
Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Department of Biology, Penn State University, State College, Pennsylvania; and.
Lu
L
Sun
Brain Science Laboratory, The Research Organization of Science and Technology, Ritsumeikan University, Kyoto, Japan.
Masayoshi
M
Mishina
Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, Louisiana; Department of Biology, Penn State University, State College, Pennsylvania; and sliu@lsuhsc.edu.
Siqiong June
SJ
Liu
D000818:Animals; D002531:Cerebellum / Q000502:physiology*; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology; D018698:Glutamic Acid / Q000502:physiology*; D007395:Interneurons / Q000502:physiology*; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
C121001:NR2B NMDA receptor; C464436:NR2D NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
GABA release; LTP; NMDA receptors; cerebellum; inhibitory interneurons