Abstract
P21-activated kinase 3 (PAK3) gene mutations are linked to several neurodevelopmental disorders, but the underlying mechanisms remain unclear. In this study, we used a tetracycline-inducible system to control the expression of a mutant PAK3 (mPAK3) protein in immediate early gene, namely cFos, positive cells to disrupt PAK signaling, specifically in cells activated by social interaction in transgenic mice. We show that the expression of mPAK3-GFP proteins was in cFos-expressing excitatory and inhibitory neurons in various brain regions, such as the cortex and hippocampus, commonly activated during learning and memory. Basal expression of mPAK3-GFP proteins in cFos-positive cells resulted in social recognition memory deficits in the three-chamber social interaction test, without affecting locomotor activity or other forms of memory. The social memory deficit was rescued by doxycycline to halt the mPAK3-GFP transgene expression. In addition, we show that the expression of mPAK3-GFP proteins in a subset of cFos-positive cells, induced by an antecedent short social interaction, termed social pairing, was sufficient to impair social recognition memory. These results indicate that normal PAK signaling in cFos-positive cells activated during social interaction is critical for social memory.
Highlights
Social interactions are essential for forming meaningful relationships and for maintaining physical health [1,2,3], but many psychiatric and neurodevelopmental disorders, such as autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia, result in impaired social skills [4,5,6] that are currently without an effective treatment or cure
Using the tetracycline-inducible system, we have previously shown that expression of a mutant p21-activated kinase 3 (PAK3) (R67)-GFP protein in the excitatory neurons of the entorhinal–hippocampal (EC-HPC) circuit impaired social recognition memory without affecting other behaviors [17]
We found that mutant PAK3 (mPAK3)-GFP-expressing cells in double transgenic mouse line (dTg) animals co-localized mostly with neurons (Figure 2A, 89.41 ± 1.831%) and double transgenic; tetO‐sTg, tetO‐mPAK3‐GFP single transgenic; tTA‐sTg, Fos‐tTA single trans‐ genic; CA1, cornus ammonis 1; CA3, cornus ammonis 3; DG, dentate gyrus; ML, molecular layer; GCL, granule cell layer
Summary
Social interactions are essential for forming meaningful relationships and for maintaining physical health [1,2,3], but many psychiatric and neurodevelopmental disorders, such as autism spectrum disorder (ASD), intellectual disability (ID), and schizophrenia, result in impaired social skills [4,5,6] that are currently without an effective treatment or cure. Mouse models generated based on the manipulations of PAK3 and its close family members display impaired synaptic function, including spine morphology and synaptic plasticity, as well as cognitive deficits, without alterations in the gross anatomy of the brain, as seen in human patients [12,13,14,15,16,17]. These animal models provide powerful tools for investigating the molecular processes underlying cognitive deficits
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