title: Specific contributions of N-methyl-D-aspartate receptors in the dorsal striatum to cognitive flexibility.
abstract: Behavioral flexibility is known to be mediated by corticostriatal systems and to involve several major neurotransmitter signaling pathways. The current study investigated the effects of inactivation of glutamatergic N-methyl-D-aspartate-(NMDA) receptor signaling in the dorsal striatum on behavioral flexibility in mice. NMDA-receptor inactivation was achieved by virus-mediated inactivation of the Grin1 gene, which encodes the essential NR1 subunit of NMDA receptors. To assess behavioral flexibility, we used a water U-maze paradigm in which mice had to shift from an initially acquired rule to a new rule (strategy shifting) or had to reverse an initially learned rule (reversal learning). Inactivation of NMDA-receptors in all neurons of the dorsal striatum did not affect learning of the initial rule or reversal learning, but impaired shifting from one strategy to another. Strategy shifting was also compromised when NMDA-receptors were inactivated only in dynorphin-expressing neurons in the dorsal striatum, which represent the direct pathway. These data suggest that NMDA-receptor-mediated synaptic plasticity in the dorsal striatum contributes to strategy shifting and that striatal projection neurons of the direct pathway are particularly relevant for this process.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, United States. Electronic address: mdarvas@uw.edu.
authors.forename: M
authors.initials: M
authors.lastname: Darvas
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98104, United States; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98104, United States.
authors.forename: R D
authors.initials: RD
authors.lastname: Palmiter
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism*; D004399:Dynorphins / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D056344:Executive Function / Q000502:physiology*; D005106:Exploratory Behavior / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012193:Reversal Learning / Q000502:physiology*
chemical_list: D004745:Enkephalins; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D016194:Receptors, N-Methyl-D-Aspartate; D004399:Dynorphins; C033660:preproenkephalin
keywords: direct pathway; executive function; knockout; learning; medium spiny neuron; plasticity