Synapsin II gene expression in the dorsolateral prefrontal cortex of brain specimens from patients with schizophrenia and bipolar disorder: effect of lifetime intake of antipsychotic drugs.

Synapsins are neuronal phosphoproteins crucial to regulating the processes required for normal neurotransmitter release. Synapsin II, in particular, has been implied as a candidate gene for schizophrenia. This study investigated synapsin II mRNA expression, using real-time reverse transcriptase-PCR, in coded dorsolateral prefrontal cortical samples provided by the Stanley Foundation Neuropathology Consortium. Synapsin IIa was decreased in patients with schizophrenia when compared with both healthy subjects and patients with bipolar disorder, whereas synapsin IIb was only significantly reduced in patients with schizophrenia when compared with healthy subjects but not in patients with bipolar disorder. Furthermore, lifetime antipsychotic drug use was positively associated with synapsin IIa expression in patients with schizophrenia. Results suggest that impairment of synaptic transmission by synapsin II reduction may contribute to dysregulated convergent molecular mechanisms, which result in aberrant neural circuits that characterize schizophrenia, while implicating involvement of synapsin II in therapeutic mechanisms of currently prescribed antipsychotic drugs.

Effects of MK-801 treatment across several pre-clinical analyses including a novel assessment of brain metabolic function utilizing PET and CT fused imaging in live rats.

BACKGROUND: Functional imaging studies in schizophrenic patients have demonstrated metabolic brain abnormalities during cognitive tasks. This study aimed to 1) introduce a novel analysis of brain metabolic function in live animals to characterize the hypo- and hyperfrontality phenomena observed in schizophrenia and following NMDA antagonist exposure, and 2) identify a robust and representative MK-801 treatment regimen that effectively models brain metabolic abnormalities as well as a range of established behavioural abnormalities representative of schizophrenia. METHODS: The validity of the MK-801 animal model was examined across several established pre-clinical tests, and a novel assessment of brain metabolic function using PET/CT fused imaging. In the present study, MK-801 was administered acutely at 0.1 mg/kg and 0.5 mg/kg, and sub-chronically at 0.5 mg/kg daily for 7 days. RESULTS: Acute treatment at 0.5 mg/kg-disrupted facets of memory measured through performance in the 8-arm radial maze task and generated abnormalities in sensorimotor gating, social interaction and locomotor activity. Furthermore, this treatment regimen induced hyperfrontality (increased brain metabolic function in the prefrontal area) observed via PET/CT fused imaging in the live rat. LIMITATIONS: While PET and CT fused imaging in the live rat offers a functional representation of metabolic function, more advanced PET/CT integration is required to analyze more discrete brain regions. CONCLUSION: These findings provide insight on the effectiveness of the MK-801 pre-clinical model of schizophrenia and provide an optimal regimen to model schizophrenia. PET/CT fused imaging offers a highly translatable tool to assess hypo- and hyperfrontality in live animals.