A thalamo-hippocampal-ventral tegmental area loop may produce the positive feedback that underlies the psychotic break in schizophrenia

Abstract

The N-methyl-D-aspartate receptor (NMDAR) hypofunction model of schizophrenia is based on the ability of NMDAR antagonists to produce many symptoms of the disease. Recent work in rats shows that NMDAR antagonist works synergistically with dopamine to produce delta frequency bursting in the thalamus. This finding, together with other results in the literature, suggests a mechanism for the sudden onset of schizophrenia. Among the thalamic nuclei most activated by NMDAR antagonist is the nucleus reuniens. This nucleus excites the cornu ammonis area 1 (CA1) region of the hippocampus. Experiments indicate that such activation can lead to excitation of dopaminergic cells of the ventral tegmental area by a polysynaptic pathway. The resulting elevation of dopamine in the thalamus will enhance thalamic bursting, thereby creating a loop with the potential for positive feedback. We show through computer simulations that in individuals with susceptibility to schizophrenia (e.g., because of partially compromised NMDAR function), an event that stimulates the dopamine system, such as stress, can cause the system to reach the threshold for thalamic bursting. When this occurs, positive feedback in the loop will cause all components to become highly active and to remain active after the triggering stimulus is removed. This is a physiologically specific hypothesis for the sudden and lasting transition that underlies the psychotic break in schizophrenia. Furthermore, the model provides an explanation for the observed selective activation of the CA1 hippocampal region in schizophrenia. The model also predicts an increase of basal activity in the dopamine system and thalamus; the relevant evidence is reviewed.

Figure 1

NMDAR blockers cause delta frequency oscillations in the cortex by an effect on thalamus. A. The effect of systemic injections of NMDAR antagonist on cortical EEG can be reproduced by intrathalamic microinjection of antagonist. Extracted with permission from Fig. 6 in (16). B. Application of NMDAR blocker (APV) to cells in the thalamic reticular nucleus in vitro causes a switch from regular firing to bursting at delta frequency (receptor activation is by ambient glutamate). Blockade of D2 dopamine receptors by eticlopride reverses the effect (receptor activation is by ambient dopamine). Extracted with permission from Fig. 6 in (15).

Figure 2

Activation of relevant brain structures by MK801 in vivo. c-Fos expression in ventral tegmental area (VTA) (A), nucleus reuniens (Re) (B), and CA1 hippocampal region (C) 4 hours after drug application. Nucleus reticularis was also activated (not shown). There was no c-Fos expression in CA3 (C). Extracted with permission from Fig. 1 and 2 in (28). D, E. The synaptic uptake of 2-DG 4 min after saline (D) and MK801 administration (E) shows strong increase of synaptic activity in medial prefrontal cortex (MPC), in stratum lacunosum-moleculare of CA1 (SLM), and in the subiculum (Sub). Inferior colliculus (IC) activity is decreased by MK801. Extracted with permission from Fig. 3 in (37).

Figure 3

Hippocampus (CA1), thalamus, and VTA form a bistable network in which each region stimulates the next region in the loop (arrows). Hippocampal firing is regulated by a feedback inhibition from interneurons. The nRT and relay cells of the thalamus are assumed to have similar bursting patterns.

Figure 4

Computer simulations of loop activity in response to predisposition to schizophrenia (NMDAR hypofunction), stress, or the combination. Hyperactivity in the loop is reached when stress occurs in the presence of predisposition. Positive feedback maintains the activity even after the stress is removed, demonstrating bistability in the presence of predisposition. [AU] – Arbitrary units.