d-Serine administration affects nitric oxide synthase 1 adaptor protein and DISC1 expression in sex-specific manner

Abstract

Antipsychotic medications are inefficient at treating symptoms of schizophrenia (SCZ), and N-methyl d-aspartate receptor (NMDAR) agonists are potential therapeutic alternatives. As such, these agonists may act on different pathways and proteins altered in the brains of patients with SCZ than do antipsychotic medications. Here, we investigate the effects of administration of the antipsychotic haloperidol and NMDAR agonist d-serine on function and expression of three proteins that play significant roles in SCZ: nitric oxide synthase 1 adaptor protein (NOS1AP), dopamine D2 (D2) receptor, and disrupted in schizophrenia 1 (DISC1). We administered haloperidol or d-serine to male and female Sprague Dawley rats via intraperitoneal injection for 12 days and subsequently examined cortical expression of NOS1AP, D2 receptor, and DISC1. We found sex-specific effects of haloperidol and d-serine treatment on the expression of these proteins. Haloperidol significantly reduced expression of D2 receptor in male, but not female, rats. Conversely, d-serine reduced expression of NOS1AP in male rats and did not affect D2 receptor expression. d-serine treatment also reduced expression of DISC1 in male rats and increased DISC1 expression in female rats. As NOS1AP is overexpressed in the cortex of patients with SCZ and negatively regulates NMDAR signaling, we subsequently examined whether treatment with antipsychotics or NMDAR agonists can reverse the detrimental effects of NOS1AP overexpression in vitro as previously reported by our group. NOS1AP overexpression promotes reduced dendrite branching in vitro, and as such, we treated cortical neurons overexpressing NOS1AP with different antipsychotics (haloperidol, clozapine, fluphenazine) or d-serine for 24 h and determined the effects of these drugs on NOS1AP expression and dendrite branching. While antipsychotics did not affect NOS1AP protein expression or dendrite branching in vitro, d-serine reduced NOS1AP expression and rescued NOS1AP-mediated reductions in dendrite branching. Taken together, our data suggest that d-serine influences the function and expression of NOS1AP, D2 receptor, and DISC1 in a sex-specific manner and reverses the effects of NOS1AP overexpression on dendrite morphology.

Förster resonance energy transfer efficiency of the vinculin tension sensor in cultured primary cortical neuronal growth cones

“…Cortices were dissected from embryonic rat brains at gestational day 18 as previously described 36 , 37 and in accordance with protocols approved by the Rutgers Animal Care and Facilities Committee and the National Institutes of Health guide for the care and use of Laboratory animals (Rutgers Institutional AAALAC Accreditation Number: 000534). Tissue was triturated, and neurons were dissociated and cultured.…”

D-Serine: Potential Therapeutic Agent and/or Biomarker in Schizophrenia and Depression?

“…Svane etal. (55) administered D-serine to male and female rats and measured expression of nitric oxide synthase1 adaptor protein (NOS1AP) (overexpressed in cortex of patients with schizophrenia), D2 receptors and DISC1 and found that it affects expression of these three genes in a sex-specific manner. Mustafa etal.…”

Nitric oxide and sex differences in dendritic branching and arborization

“…For example, recall when NOS1AP is overexpressed, dendritic arborization decreases (Wang et al., 2016). However, activation of NMDAR with the agonist d ‐serine has been found to decrease the expression of NOS1AP in male but not in female rats, restoring the dendritic branching that NOS1AP inhibits in rat cortical neurons (Svane et al., 2018). This study provides evidence that sex differences in NO signaling via the nNOS binding partner, NOS1AP, may underlie some of the sex differences seen in dendritic patterning of developing neurons.…”