Recent studies on the phosphoprotein synapsin II have revealed reduced expression in postmortem medial prefrontal cortex tissues from subjects with schizophrenia, and chronic antipsychotic drug treatment has resulted in concurrent increases in synapsin II mRNA and protein levels. Collectively, this research suggests a role of synapsin II in the pathophysiology of schizophrenia; however, whether synapsin II plays a causal role in this disease process still remains unclear. Therefore, the goal of this investigation was to examine whether synapsin II knockout mice display behavioral abnormalities commonly expressed in preclinical animal models of schizophrenia, namely deficits in prepulse inhibition (PPI), decreased social behavior, and locomotor hyperactivity. Results indicate that mice with knockout of the synapsin II gene demonstrate deficits in PPI at three prepulse intensities (67, 70, and 73 dB), along with deficits in habituation to startle to a 110 dB acoustic pulse. Knockout animals also expressed decreased social behavior and increased locomotor activity when compared to wildtype and heterozygous populations. Complete knockout of the synapsin II gene was confirmed in postmortem brain tissues via immunoblotting. In conclusion, these results confirm that synapsin II knockout mice display behavioral endophenotypes similar to established preclinical animal models of schizophrenia, and lend support to the notion that abnormalities in synapsin II expression may play a causal role in the underlying pathophysiological mechanisms of schizophrenia.

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Clozapine is an atypical antipsychotic drug with unique pharmacological and therapeutic properties. Unlike the typical antipsychotic drug, haloperidol, clozapine does not cause extrapyramidal side effects; however, weight gain, dyslipidemia, and type II diabetes are commonly associated with the use of this drug in subjects with schizophrenia. The aim of this study was to profile gene expression in the rat striatum following clozapine treatment. Chronic treatment with clozapine revealed upregulation of several genes including the glucose-dependent insulinotropic polypeptide (GIP) gene by over 200% in the rat striatum. The cDNA array results for the GIP gene were confirmed by real-time RT-PCR as well as by radioimmunoassay. Expression of the GIP gene in the central nervous system is consistent with the results of retinal GIP gene expression as reported by other investigators. Taken together, these findings implicate the possible role of GIP as a neuromodulator in the central nervous system. GIP is an insulinotropic agent with stimulatory effects on insulin synthesis and release from the pancreas. However, changes in brain GIP levels are most likely unrelated to the metabolic adverse effects (dyslipidemia, type II diabetes, weight gain) associated with clozapine treatment. Therefore, we also measured GIP gene expression in the K-cell-rich regions, duodenum and jejunum (small intestine), and plasma GIP levels using radioimmunoassay following chronic treatment with clozapine. GIP mRNA levels in the small intestine and the plasma GIP at the protein level were significantly elevated in clozapine-treated subjects. Furthermore, as observed in humans, chronic clozapine treatment also caused weight gain, and increased levels of insulin, triglycerides and leptin in the plasma. These results suggest that adverse metabolic effects associated with clozapine treatment may be related to its ability to increase intestinal gene expression for GIP.

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 RT-PCR, in coded dorsolateral prefrontal cortical samples provided by the Stanley Foundation Neuropathology Consortium. Synapsin IIa was decreased in patients with schizophrenia when compared to both healthy subjects and patients with bipolar disorder, whereas the synapsin IIb was only significantly reduced in patients with schizophrenia when compared to healthy subjects, but not 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.

Synapsins are a family of neuron-specific phosphoproteins involved in synaptic vesicle docking, synaptogenesis, and synaptic plasticity. Previous studies have reported an increase in synapsin II protein by dopaminergic agents in the striatum, medial prefrontal cortex, and nucleus accumbens. This study investigated the mechanistic pathway involved in synapsin II regulation by dopaminergic drugs using primary midbrain neurons to determine which of several transcription factors regulates synapsin II expression. Protein kinase A (PKA) participation in the signaling pathway was examined using selective PKA inhibitors, which reduced synapsin II expression in cell cultures while dopaminergic agents were unable to increase synapsin II in the presence of the PKA inhibitor. Transcription factor involvement was further investigated using separate cultures treated with antisense deoxyoligonucleotides (ADONs) against the following transcription factors: activating protein 2 alpha (AP-2alpha), early growth response factor 1 (EGR-1), or polyoma enhancer activator-3 (PEA-3). Selective knockdown of AP-2alpha by ADONs reduced synapsin II levels, whereas treatment with EGR-1 and PEA-3 ADONs did not affect synapsin II expression. Furthermore, dopaminergic agents were no longer able to influence synapsin II concentrations following AP-2alpha knockdown. Collectively, these results indicate that a cyclic adenosine-3',5'-monophosphate/PKA-dependent mechanism involving the AP-2alpha transcription factor is likely responsible for the increase in neuronal synapsin II following dopamine D1 receptor stimulation or dopamine D2 receptor inhibition.