Ultrastructural evidence for glutamatergic dysregulation in schizophrenia.

The aim of this paper is to summarize ultrastructural evidence for glutamatergic dysregulation in several linked regions in postmortem schizophrenia brain. Following a brief summary of glutamate circuitry and how synapses are identified at the electron microscopic (EM) level, we will review EM pathology in the cortex and basal ganglia. We will include the effects of antipsychotic drugs and the relation of treatment response. We will discuss how these findings support or confirm other postmortem findings as well as imaging results. Briefly, synaptic and mitochondrial density in anterior cingulate cortex was decreased in schizophrenia, versus normal controls (NCs), in a selective layer specific pattern. In dorsal striatum, increases in excitatory synaptic density were detected in caudate matrix, a compartment associated with cognitive and motor function, and in the putamen patches, a region associated with limbic function and in the core of the nucleus accumbens. Patients who were treatment resistant or untreated had significantly elevated numbers of excitatory synapses in limbic striatal areas in comparison to NCs and responders. Protein levels of vGLUT2, found in subcortical glutamatergic neurons, were increased in the nucleus accumbens in schizophrenia. At the EM level, schizophrenia subjects had an increase in density of excitatory synapses in several areas of the basal ganglia. In the substantia nigra, the protein levels of vGLUT2 were elevated in untreated patients compared to NCs. The density of inhibitory synapses was decreased in schizophrenia versus NCs. In schizophrenia, glutamatergic synapses are differentially affected depending on the brain region, treatment status, and treatment response.