title: Loss of GluN2A-containing NMDA receptors impairs extra-dimensional set-shifting.
abstract: Glutamate neurotransmission via the N-methyl-D-aspartate receptor (NMDAR) is thought to mediate the synaptic plasticity underlying learning and memory formation. There is increasing evidence that deficits in NMDAR function are involved in the pathophysiology of cognitive dysfunction seen in neuropsychiatric disorders and addiction. NMDAR subunits confer different physiological properties to the receptor, interact with distinct intracellular postsynaptic scaffolding and signaling molecules, and are differentially expressed during development. Despite these known differences, the relative contribution of individual subunit composition to synaptic plasticity and learning is not fully elucidated. We have previously shown that constitutive deletion of GluN2A subunit in the mouse impairs discrimination and re-learning phase of reversal when exemplars are complex picture stimuli, but spares acquisition and extinction of non-discriminative visually cued instrumental response. To investigate the role of GluN2A containing NMDARs in executive control, we tested GluN2A knockout (GluN2A(KO) ), heterozygous (GluN2A(HET) ) and wild-type (WT) littermates on an attentional set-shifting task using species-specific stimulus dimensions. To further explore the nature of deficits in this model, mice were tested on a visual discrimination reversal paradigm using simplified rotational stimuli. GluN2A(KO) were not impaired on discrimination or reversal problems when tactile or olfactory stimuli were used, or when visual stimuli were sufficiently easy to discriminate. GluN2A(KO) showed a specific and significant impairment in ventromedial prefrontal cortex-mediated set-shifting. Together these results support a role for GluN2A containing NMDAR in modulating executive control that can be masked by overlapping deficits in attentional processes during high task demands.
authors: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.
authors: K
authors: K
authors: Marquardt
authors: M
authors: M
authors: Saha
authors: M
authors: M
authors: Mishina
authors: J W
authors: JW
authors: Young
authors: J L
authors: JL
authors: Brigman
mesh_terms: D000818:Animals; D001288:Attention; D003071:Cognition; D004192:Discrimination, Psychological; D056344:Executive Function; D005260:Female; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000378:metabolism / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate
keywords: Executive function; GluN2A; MDAR; mouse models; set-shifting