NMDA receptor antagonists attenuate the proconvulsant effect of juvenile social isolation in male mice

• Applying juvenile SIS increased susceptibility to PTZ-induced seizure.
• NMDA receptor antagonists reversed the proconvulsant effect of SIS.
• NOS inhibitors potentiated the anticonvulsant effects of NMDA receptor antagonists.
• SIS upregulated NR2B subunit of NMDA receptor in the hippocampus.
• Dysregulation of hippocampal NMDA/NO pathway is involved in proconvulsant effects of SIS.

Experiencing psychosocial stress in early life, such as social isolation stress (SIS), is known to have negative enduring effects on the development of the brain and behavior. In addition to anxiety and depressive-like behaviors, we previously showed that juvenile SIS increases susceptibility to pentylenetetrazole (PTZ)-induced seizures in mice through enhancing the nitrergic system activity in the hippocampus. In this study, we investigated the possible involvement of N-methyl-d-aspartate (NMDA) receptors in proconvulsant effects of juvenile SIS. Applying 4 weeks of SIS to juvenile male mice at postnatal day 21–23, we observed an increased susceptibility to PTZ as well as anxiety and depressive-like behaviors in adult mice. Intraperitoneal (i.p.) administration of NMDA receptor antagonists, MK-801 (0.05 mg/kg) and ketamine (0.5 mg/kg), reversed the proconvulsant effects of SIS in Isolated (and not social) housed animals. Co-administration of non-effective doses of nitric oxide synthase (NOS) inhibitors, 7NI (25 mg/kg) and L-NAME (10 mg/kg), with NMDA receptor antagonists, MK-801 (0.01 mg/kg) and ketamine (0.1 mg/kg) attenuated the proconvulsant effects of juvenile SIS only in isolated housed mice. Also, using real time RT-PCR, we showed that hippocampal upregulation of NR2B subunit of NMDA receptor may play a critical role in proconvulsant effects of juvenile SIS by dysregulation of NMDA/NO pathway. In conclusion, results of present study revealed that experiencing SIS during adolescence predisposes the co-occurrence of seizure disorders with psychiatric comorbidities and also, alteration of NMDA receptor structure and function in hippocampus plays a role in proconvulsant effects of juvenile SIS through enhancing the NMDA/NO pathway.