Cortical development and glutamatergic dysregulation in schizophrenia.

摘要

Brains of patients with schizophrenia (SZ) show both anatomical and functional deficits that suggest aberrant glutamate neurotransmission. Historically, many studies have addressed neurochemical changes in glutamate and its metabolites in various brain regions and cerebrospinal fluid in patients with SZ and compared them with those in normal control subjects. Alteration in molecular disposition associated with glutamate signaling has also been addressed by receptor binding assays. Although all such results are not perfectly in complete accord, an approach with 1H magnetic resonance spectroscopy (MRS) indicates more consistently that the levels of N-acetylaspartate (NAA)-a marker associated with glutamate synapses and signaling-are decreased in SZ brains, especially in the frontal cortex, temporal cortex, and thalamus (1). More recent genetic studies and molecular expression profiling have supported the notion of disturbed neurotransmission and synaptic connectivity (2). Genetic susceptibility factors for SZ identified through association study and cyto-genetic approaches are enriched in the dendritic spine, the key postsynaptic structure, including Neuregulin-1, ErbB4, and regulator of G-protein signaling 4. Microarray analysis, an unbiased method for gene expression profiling, also provides evidence that expression of synaptic molecules is decreased in SZ. A decrease in dendritic spines is reported in SZ (2,3), consistent with these findings.