Proteome analysis after co-administration of clozapine or haloperidol to MK-801-treated rats.

MK-801, a glutamergic, N-methyl-D-aspartate (NMDA)-receptor antagonist that mediates neurotransmission and has psychotomimetic properties, giving schizophrenia-like symptom. The objective of this study was to investigate the effects on the thalamic and cortical proteome of one typical (haloperidol) and one atypical (clozapine) antipsychotic drug in interaction with MK-801 in rats. Rats received subcutaneous injections of MK-801 or vehicle (controls) or MK-801 together with concurrent administration of haloperdol or clozapine for eight days. Protein samples from thalamus and cortex were analyzed with two-dimensional gel electrophoresis in combination with mass spectrometry. MK-801 induced alterations in the levels of three proteins in both cortex and thalamus. Clozapine reversed all the protein changes. Haloperidol reversed two. Both antipsychotics induced new protein changes in both cortex and thalamus not seen after MK-801-treatment by alone. In conclusion, the MK-801 animal model shows potential for investigation of different antipsychotic drugs and biochemical treatment effects in schizophrenia.

The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains.

Two synaptic-vesicle proteins, rab3a and synaptophysin, have been studied on post-mortem brain tissues of schizophrenics and healthy controls. We found significantly reduced levels of rab3a in thalamus (p<0.001); for both proteins in gyrus cinguli and hippocampus (p<0.0001); for rab3a in frontal and parietal cortex (p<0.05); and no differences in temporal cortex or cerebellum in schizophrenics compared with controls. Reduced synaptic density may be a prominent feature of the molecular neuropathology of schizophrenia.

Reduction of the small synaptic vesicle protein synaptophysin but not the large dense core chromogranins in the left thalamus of subjects with schizophrenia.

BACKGROUND: It has been hypothesized that a lesion in the neuronal circuits of thalamus might contribute to the symptoms in schizophrenia. It has also been suggested that impaired synaptic transmission is an important component of the pathophysiology of schizophrenia. In the present study we assess the synaptic integrity of thalamus by means of examining the protein levels of: (1) synaptophysin, a membrane bound protein of small synaptic vesicles, and (2) chromogranins, a family of soluble secretory proteins stored and released from the secretory large dense-core vesicles. METHODS: The brains of 9 patients with schizophrenia and 9 age-matched control subjects were studied. The levels of synaptophysin and chromogranins were measured by radioimmunoassays. RESULTS: The amount of synaptophysin in the left thalamus was significantly decreased (p = .036) in the schizophrenic group (2655 +/- 605 nmol synaptophysin/mg total protein) compared to the control group (3248 +/- 827 nmol synaptophysin/mg total protein). There were no differences between the groups in the levels of chromogranins, nor in the levels of synaptophysin of the right thalamus. CONCLUSIONS: These findings indicate defect synaptic function in the left thalamus of patients with schizophrenia. This may be the cause of a reduction of synaptic terminals or a defect limited to certain structures of the synapse, namely the small presynaptic vesicles.