NMDA receptor hypofunction and the thalamus in schizophrenia

Abstract

The thalamus can be subdivided into two kinds of nuclei, the higher order (HO) and the first order (FO) relays, which are distinguished based on the origin of their main or driver inputs. The driver inputs to the HO nuclei arrive from the cortex, and the messages they deliver are then relayed to other cortical areas. As the origin of these inputs is the cortical layer V, whose axons branch and innervate lower motor centers in the CNS, the messages are copies of motor instructions issued to those lower motor centers. These copies are thus an integral part of perceptual processes. In schizophrenia, the HO nuclei are shrunken suggesting that a reduced ability to integrate copies of ongoing motor commands in perceptual processes may be one part of the underlying pathophysiology. The driver inputs in the thalamus utilize ionotropic glutamate receptors such as the NMDAR. NMDAR antagonists may exert their pro-psychotic effects by impairing the function of the HO nuclei. Here, we argue that such agents (or the proposed NMDAR hypofunction in schizophrenia) weaken the driver inputs in the HO nuclei, thereby producing a cortico-thalamo-cortical disconnection and impairing sensorimotor integration.

Keywords: Higher order thalamic nuclei; NMDAR; Psychosis; Sensorimotor gating.