Abstract
Proper communication between neurons depends upon appropriate patterning of dendrites and correct distribution and structure of spines. Schizophrenia is a neuropsychiatric disorder characterized by alterations in dendrite branching and spine density. Nitric oxide synthase 1 adaptor protein (NOS1AP), a risk gene for schizophrenia, encodes proteins that are upregulated in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. To elucidate the effects of NOS1AP overexpression observed in individuals with schizophrenia, we investigated changes in actin dynamics and spine development when a long (NOS1AP-L) or short (NOS1AP-S) isoform of NOS1AP is overexpressed. Increased NOS1AP-L protein promotes the formation of immature spines when overexpressed in rat cortical neurons from day in vitro (DIV) 14 to DIV 17 and reduces the amplitude of miniature excitatory postsynaptic currents (mEPSCs). In contrast, increased NOS1AP-S protein increases the rate of actin polymerization and the number of immature and mature spines, which may be attributed to a decrease in total Rac1 expression and a reduction in the levels of active cofilin. The increase in the number of mature spines by overexpression of NOS1AP-S is accompanied by an increase in the frequency of mEPSCs. Our findings show that overexpression of NOS1AP-L or NOS1AP-S alters the actin cytoskeleton and synaptic function. However, the mechanisms by which these isoforms induce these changes are distinct. These results are important for understanding how increased expression of NOS1AP isoforms can influence spine development and synaptic function.
Highlights
Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) was originally identified as a negative regulator of the interaction between the enzyme neuronal nitric oxide synthase (NOS1; nNOS) and PSD-95 (Jaffrey et al, 1998)
We have previously shown that the expression of NOS1APL and NOS1AP-S is upregulated in postmortem tissue from the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia (Hadzimichalis et al, 2010)
We reported that NOS1AP-L and NOS1AP-S regulate dendrite branching (Carrel et al, 2009), and others reported that NOS1AP-L regulates dendritic spine development (Richier et al, 2010) in rat hippocampal neurons
Summary
Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) was originally identified as a negative regulator of the interaction between the enzyme neuronal nitric oxide synthase (NOS1; nNOS) and PSD-95 (Jaffrey et al, 1998). Since schizophrenia is believed to be a neurodevelopmental disorder (Benes, 1991; Murray et al, 1991; Bunney et al, 1995; Brent et al, 2014), in the present study, we investigate the effects of overexpression of these isoforms on actin dynamics, dendritic spine number and morphology, and resulting electrophysiology. We report that both NOS1AP-L and NOS1AP-S associate with filamentous actin (F-actin) and that increased protein levels of NOS1AP-L or NOS1AP-S result in reorganization of the actin cytoskeleton. The overexpression of NOS1AP-S results in the down regulation of Rac protein expression and reduced levels of the active, non-phosphorylated form of cofilin
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