Losing your inhibition: linking cortical GABAergic interneurons to schizophrenia

Abstract

GABAergic interneurons of the cerebral cortex (cINs) play crucial roles in many aspects of cortical function. The diverse types of cINs are classified into subgroups according to their morphology, intrinsic physiology, neurochemical markers and synaptic targeting. Recent advances in mouse genetics, imaging and electrophysiology techniques have greatly advanced our efforts to understand the role of normal cIN function and its dysfunction in neuropsychiatric disorders. In schizophrenia (SCZ), a wealth of data suggests that cIN function is perturbed, and that interneuron dysfunction may underlie key symptoms of the disease. In this review, we discuss the link between cINs and SCZ, focusing on the evidence for GABAergic signaling deficits from both SCZ patients and mouse models.

Figure 1

Schematic depicting a simplified cortical circuit (A) and some of the cortical interneuron (cIN)-related changes that are reported in SCZ patients (B). Sst, PV, GAD67 and GAT1 expression are reduced in SCZ patients. Postmortem studies reveal an increase in GABA_A 2 receptors at chandelier cell synapses onto pyramidal cells (1), a decrease in GABA_A 1 receptors at basket cell synapses onto pyramidal cells (2), and a decrease of NMDA receptors (NR2A subunit, in particular) at excitatory synapses onto PV⁺ cINs (3). Although only pyramidal synapses onto basket cells are shown, the reduction of NMDA receptors may also occur at synapses onto chandelier cells.