Abstract
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.
Highlights
The N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a glutamate- and glycine-gated ion channel composed of four subunits: two obligatory GluN1 subunits and a combination of GluN2 or GluN3 family subunits [1]
We report that GluN1 knock-down (GluN1KD) mice showed an age-dependent decrease of dendritic spine density in striatal medium spiny neurons (MSNs)
No sex differences were observed in striatal WAVE-1 protein level when assessed with a preliminary Scheirer-Ray-Hare test that included sex as an additional independent variable (S1 Table) Our results indicate that GluN1KD mice have reduced WAVE-1 levels and that the WASF1 transgene is sufficient to rescue striatal WAVE-1 levels in GluN1KD mice
Summary
The N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a glutamate- and glycine-gated ion channel composed of four subunits: two obligatory GluN1 subunits and a combination of GluN2 or GluN3 family subunits [1]. De novo point mutations in GluN1 or GluN2 subunits have been identified in patients with schizophrenia, autism, intellectual disability, and epilepsy [2]. Cognitive impairments are prominent features of these neurological disorders. The consequences of NMDAR hypofunction can be studied using GluN1 knock-down (GluN1KD) mice, which have a global genetic reduction of NMDARs by more than 90% [3].
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