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

• Published in: Molecular and cellular neuroscience Vol. 89; pp. 20 - 32
• Main Authors: Svane, Kirsten C., Asis, Ericka-Kate, Omelchenko, Anton, Kunnath, Ansley J., Brzustowicz, Linda M., Silverstein, Steven M., Firestein, Bonnie L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2018
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Antipsychotic Agents - pharmacology; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Female; Haloperidol - pharmacology; Isomerism; Male; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurons - metabolism; Rats; Rats, Sprague-Dawley; Serine - chemistry; Serine - pharmacology; Sex Factors
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2018.03.011

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. [Display omitted] •Haloperidol treatment does not affect NOS1AP expression in vivo and in vitro.•Haloperidol affects D2 receptor expression in vivo in sex-specific manner.•d-Serine treatment reduces NOS1AP expression in vivo in male rat cortex.•d-Serine affects DISC1 expression in sex-specific manner but does not affect D2R.•d-Serine rescues NOS1AP-induced reductions in dendrite branching in vitro.