Amygdalocortical circuitry in schizophrenia: from circuits to molecules

Schizophrenia is a disorder in which disturbances in the integration of emotion with cognition plays a central role and probably involves several different regions, including the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the hippocampal formation, and basolateral amygdala (BLA). Recent brain imaging studies have reported changes in volume, whereas postmortem studies point to dysfunction of the GABA and glutamate systems in these regions. Microarray-based profiles indicate that complex changes in the expression of genes associated with synaptic transmission and ion channels are involved in GABA cell dysfunction in schizophrenics. Molecular abnormalities vary considerably on the basis of sector and layer, suggesting that the unique connectivity of intrinsic and extrinsic afferents may critical in regulating the activity of genes in specific subpopulations of GABA cells. Projections of the BLA may be of particular importance to the induction of abnormal circuitry in schizophrenia, as their ingrowth during late adolescence and early adulthood may help to 'trigger' the onset of illness in susceptible individuals. A preponderance of cellular and molecular abnormalities has been found in the stratum oriens (SO) of sectors CA3/2 in which BLA afferents provide a robust innervation. These observations have lead to the development of a rodent model for the study of abnormal circuitry in this disorder. For example, single-cell recordings in hippocampal slices exposed to increased activation from the BLA have shown decreases in GABA currents in pyramidal neurons in SO of CA3/2, but not CA1, and support the validity of this model. Overall, the postmortem studies of neural circuitry abnormalities in schizophrenia are beginning to implicate specific cellular, molecular, and electrophysiological mechanism in specific subtypes of cortical neurons defined by their afferent and efferent connectivity within key corticolimbic regions.