Restoring striatal WAVE-1 improves maze exploration performance of GluN1 knockdown mice

• Published in: PloS one 2018-10, Vol.13 (10), p.e0199341
• Main Authors: Chen, Yuxiao, Milenkovic, Marija, Horsfall, Wendy, Salahpour, Ali, Soderling, Scott H, Ramsey, Amy J
• Format: Article
• Language: English
• Subjects: Animal behavior; Animal cognition; Animals; Autism; Behavior, Animal; Biology and Life Sciences; Cdc42 protein; Cellular signal transduction; Cognition; Cognitive ability; Cognitive disorders; Crosses, Genetic; Dendritic Spines - metabolism; Density; Exploration; Exploratory Behavior; Female; Genetic aspects; Glutamate; Glutamic acid receptors (ionotropic); Hippocampus; Hippocampus - metabolism; Hybrids; Laboratory rats; Long term memory; Male; Maze Learning; Medicine and Health Sciences; Memory; Mental disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; N-Methyl-D-aspartic acid receptors; Neostriatum; Nerve Tissue Proteins - metabolism; Neuropeptides - metabolism; Pharmacology; Phenotype; Phenotypes; Proteins; Pyramidal cells; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Receptor density; Receptors; Receptors, N-Methyl-D-Aspartate - metabolism; rho GTP-Binding Proteins - metabolism; RhoA protein; Rodents; Schizophrenia; Signal Transduction; Social Sciences; Spine; Toxicology; Transgenes; Wiskott-Aldrich Syndrome Protein Family - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0199341

NMDA receptors are important for cognition and are implicated in neuropsychiatric disorders. GluN1 knockdown (GluN1KD) mice have reduced NMDA receptor levels, striatal spine density deficits, and cognitive impairments. However, how NMDA depletion leads to these effects is unclear. Since Rho GTPases are known to regulate spine density and cognition, we examined the levels of RhoA, Rac1, and Cdc42 signaling proteins. Striatal Rac1-pathway components are reduced in GluN1KD mice, with Rac1 and WAVE-1 deficits at 6 and 12 weeks of age. Concurrently, medium spiny neuron (MSN) spine density deficits are present in mice at these ages. To determine whether WAVE-1 deficits were causal or compensatory in relation to these phenotypes, we intercrossed GluN1KD mice with WAVE-1 overexpressing (WAVE-Tg) mice to restore WAVE-1 levels. GluN1KD-WAVE-Tg hybrids showed rescue of striatal WAVE-1 protein levels and MSN spine density, as well as selective behavioral rescue in the Y-maze and 8-arm radial maze tests. GluN1KD-WAVE-Tg mice expressed normalized WAVE-1 protein levels in the hippocampus, yet spine density of hippocampal CA1 pyramidal neurons was not significantly altered. Our data suggest a nuanced role for WAVE-1 effects on cognition and a delineation of specific cognitive domains served by the striatum. Rescue of striatal WAVE-1 and MSN spine density may be significant for goal-directed exploration and associated long-term memory in mice.