title: GluN3A promotes NMDA spiking by enhancing synaptic transmission in Huntington's disease models.
abstract: Age-inappropriate expression of juvenile NMDA receptors (NMDARs) containing GluN3A subunits has been linked to synapse loss and death of spiny projection neurons of the striatum (SPNs) in Huntington's disease (HD). Here we show that suppressing GluN3A expression prevents a multivariate synaptic transmission phenotype that precedes morphological signs at early prodromal stages. We start by confirming that afferent fiber stimulation elicits larger synaptic responses mediated by both AMPA receptors and NMDARs in SPNs in the YAC128 mouse model of HD. We then show that the enhancement mediated by both is fully prevented by suppressing GluN3A expression. Strong fiber-stimulation unexpectedly elicited robust NMDAR-mediated electrogenic events (termed "upstates" or "NMDA spikes"), and the effective threshold for induction was more than 2-fold lower in YAC128 SPNs because of the enhanced synaptic transmission. The threshold could be restored to control levels by suppressing GluN3A expression or by applying the weak NMDAR blocker memantine. However, the threshold was not affected by preventing glutamate spillover from synaptic clefts. Instead, long-lasting NMDAR responses interpreted previously as activation of extrasynaptic receptors by spilled-over glutamate were caused by NMDA spikes occurring in voltage clamp mode as escape potentials. Together, the results implicate GluN3A reactivation in a broad spectrum of early-stage synaptic transmission deficits in YAC128 mice; question the current concept that NMDAR mislocalization is the pathological trigger in HD; and introduce NMDA spikes as a new candidate mechanism for coupling NMDARs to neurodegeneration.
authors.affiliation: Cellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA) and Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: Kashif
authors.initials: K
authors.lastname: Mahfooz
authors.affiliation: Cellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA) and Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Marco
authors.affiliation: Cellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA) and Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Martínez-Turrillas
authors.affiliation: Cellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA) and Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: Mathan K
authors.initials: MK
authors.lastname: Raja
authors.affiliation: Cellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA) and Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pérez-Otaño
authors.affiliation: Cellular Neurobiology Laboratory, Centro de Investigación Médica Aplicada (CIMA) and Universidad de Navarra, 31008 Pamplona, Spain. Electronic address: johnfwesseling@gmail.com.
authors.forename: John F
authors.initials: JF
authors.lastname: Wesseling
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C584082:GluN3A protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D008559:Memantine
keywords: Dendritic excitability; NR3A; Upstate