Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia?

Abstract

What causes the positive, negative, and cognitive symptoms of schizophrenia? The importance of circuits is underscored by the finding that no single gene contributes strongly to the disease. Thus, some circuit abnormality to which many proteins can contribute is the likely cause. There are several major hypotheses regarding the circuitry involved: first, a change in the balance of excitation/inhibition in the prefrontal cortex (PFC); second, abnormal EEG oscillations in the gamma range; third, an increase in theta/delta EEG power related to changes in the thalamus (particularly midline nuclei); fourth, hyperactivity in the hippocampus and consequent dopamine hyperfunction; and fifth, deficits in corollary discharge. Evidence for these hypotheses will be reviewed.

Fig. 1

Interactions between brain regions proposed to produce symptoms of SZ.

Fig. 2

Evidence for medial ventral prefrontal cortex involvement in SZ and response to NMDAR antagonist. A. Regions of enhanced delta/theta power in the resting awake state in schizophrenia spectrum disorders, as measured by MEG. (Reproduced with permission from authors as originally published in [**49]). B. Regions of decreased BOLD signal (blue) in response to ketamine. (Reproduced with permission from [**50]).

Fig. 3

Evidence of special involvement of midline thalamic nuclei in SZ-related assays. A. c-fos activation in response to systemic NMDAR antagonist (Reproduced with permission from [59]). B. c-fos activation in response to neuroleptics used to treat SZ. Response is in local interneurons. (Reproduced with permission from [*74]). C. The midline group of the dorsal thalamus is labeled in this neurogranin RNA in situ hybridization image (left) from the Allen Brain Atlas. In the atlas key (right), thalamic nuclei are pink. The midline group consists of the paraventricular (PVT (PVN in B)) nucleus, the parataenial nucleus, and nucleus of reuniens (RE). Also shown in these images are the anteromedial (AM) and anteroventral (AV) thalamic nuclei. Note that A,B,C are at different magnification and at different sections through the thalamus.