Loss of GluN2A‐containing NMDA receptors impairs extra‐dimensional set‐shifting

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 neuropsy...

Full description

Saved in:
Bibliographic Details
Published in:Genes, brain and behavior brain and behavior, 2014-09, Vol.13 (7), p.611-617
Main Authors: Marquardt, K., Saha, M., Mishina, M., Young, J. W., Brigman, J. L.
Format: Article
Language:English
Subjects:
Addictions
Animals
Attention
Cognition
Cognitive ability
Discrimination (Psychology)
Executive Function
Female
GluN2A
Glutamic acid receptors (ionotropic)
Heterozygote
Intracellular signalling
Male
MDAR
Mental disorders
Mice
Mice, Inbred C57BL
mouse models
N-Methyl-D-aspartic acid receptors
Neurotransmission
Olfactory discrimination learning
Olfactory stimuli
Prefrontal cortex
Prefrontal Cortex - metabolism
Prefrontal Cortex - physiology
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - metabolism
Reversal learning
Rodents
set‐shifting
Subunit structure
Synaptic plasticity
Tactile discrimination
Visual cortex
Visual discrimination
Visual stimuli
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 (GluN2AKO), heterozygous (GluN2AHET) 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. GluN2AKO were not impaired on discrimination or reversal problems when tactile or olfactory stimuli were used, or when visual stimuli were sufficiently easy to discriminate. GluN2AKO 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. The ability to flexibly adapt behavior is essential for an organisms survival in a complex environment. Although the mechanisms underlying behavioral flexibility have not yet been fully elucidated, the NMDA receptor shows strong potential as a mediator of the cortical plasticity required for these behaviors. Our study assessed the contribution of GluN2A‐containing NMDA receptors to attentional set‐shifting, a cross‐species measure of behavioral flexibility. Testing global GluN2A knockout mice on this task, as well as a visual touch‐screen discrimination reversal learning paradigm, we demonstrate that loss of GluN2A results in a
ISSN:1601-1848
1601-183X
DOI:10.1111/gbb.12156