Abstract
PSD-Zip70 is a postsynaptic protein that regulates glutamatergic synapse formation and maturation by modulation of Rap2 activity. PSD-Zip70 knockout (PSD-Zip70KO) mice exhibit defective glutamatergic synaptic transmission in the prefrontal cortex (PFC) with aberrant Rap2 activation. As prefrontal dysfunction is implicated in the pathophysiology of stress-induced psychiatric diseases, we examined PSD-Zip70KO mice in a social defeat (SD) stress-induced mouse model of depression to investigate stress-induced alterations in synaptic function. Compared with wild-type (WT) mice, PSD-Zip70KO mice exhibited almost normal responses to SD stress in depression-related behaviors such as social activity, anhedonia, and depressive behavior. However, PSD-Zip70KO mice showed enhanced anxiety-like behavior irrespective of stress conditions. The density and size of dendritic spines of pyramidal neurons were reduced in the medial PFC (mPFC) in mice exposed to SD stress. Phosphorylation levels of the AMPA–type glutamate receptor (AMPA-R) GluA2 subunit at Ser880 were prominently elevated in mice exposed to SD stress, indicating internalization of surface-expressed AMPA-Rs and decreased postsynaptic responsiveness. Structural and functional impairments in postsynaptic responsiveness were associated with Rap2 GTPase activation in response to SD stress. Social stress-induced Rap2 activation was regulated by a PSD-Zip70-dependent pathway via interaction with SPAR/PDZ-GEF1. Notably, features such as Rap2 activation, dendritic spine shrinkage, and increased GluA2 phosphorylation were observed in the mPFC of PSD-Zip70KO mice even without SD stress. Together with our previous results, the present findings suggest that SD stress-induced postsynaptic hyporesponsiveness in glutamatergic synapses is mediated by PSD-Zip70-Rap2 signaling pathway and closely relates to anxiety-like behaviors.
Highlights
The prefrontal cortex (PFC), the dorsolateral PFC and medial PFC in humans, and the dorsal mPFC including the anterior cingulate cortex (ACC), prelimbic cortex (PrLC), and infralimbic cortex (ILC) in rodents, is critical for higher-order executive functions as well as working memory, cognition, decision making, and emotional control (Levy and Goldman-Rakic, 2000; Dumitriu et al, 2010; Etkin et al, 2011; Euston et al, 2012)
We previously reported that postsynaptic density (PSD)-Zip70 deficiency causes synaptic dysfunction with an increased proportion of small, immature dendritic spines in the mPFC (Mayanagi et al, 2015)
To clarify whether PSD-Zip70 was involved in social defeat (SD)-induced Rap2 activation, we examined the interaction of PSD-Zip70 and its binding partners, as we previously demonstrated that PSD-Zip70 regulated Rap2 activity via interaction with SPAR and PDZ-GEF1, which are PSD-Zip70interacting RapGAP (Rap GTPase activating proteins) and RapGEF (Rap guanine nucleotides exchange factor), respectively (Mayanagi et al, 2015)
Summary
The prefrontal cortex (PFC), the dorsolateral PFC (dlPFC) and medial PFC (mPFC) in humans, and the dorsal mPFC including the anterior cingulate cortex (ACC), prelimbic cortex (PrLC), and infralimbic cortex (ILC) in rodents, is critical for higher-order executive functions as well as working memory, cognition, decision making, and emotional control (Levy and Goldman-Rakic, 2000; Dumitriu et al, 2010; Etkin et al, 2011; Euston et al, 2012). MPFC volume is reduced and synaptic density in the dlPFC and mPFC is decreased in patients with major depressive disorder (MDD) (Drevets et al, 2008; Kang et al, 2012). Recent functional neuroimaging analyses indicated that lower activity of the PFC is an important factor underlying the pathophysiology of stress-related psychiatric diseases such as MDD and schizophrenia (Ragland et al, 2007; Kinou et al, 2013). Rodent models have improved our understanding of the role of the mPFC in stress-induced alterations in brain function. Chronic stress induces dendritic debranching and spine loss, resulting in reduction of mPFC volume in rodent models (Radley et al, 2004, 2008). Repeated physical stress and prolonged psychological stress evoke various behavioral alternations like MDD, such as decreased social ability, enhanced anxiety, anhedonia, and helplessness-related depressive behaviors (Cryan and Mombereau, 2004; Berton et al, 2006; Yang et al, 2015)
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