Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia

Abstract

Dysregulation of the dopamine system is central to many models of the pathophysiology of psychosis in schizophrenia. However, emerging evidence suggests that this dysregulation is driven by the disruption of upstream circuits that provide afferent control of midbrain dopamine neurons. Furthermore, stress can profoundly disrupt this regulatory circuit, particularly when it is presented at critical vulnerable prepubertal time points. This review will discuss the dopamine system and the circuits that regulate it, focusing on the hippocampus, medial prefrontal cortex, thalamic nuclei, and medial septum, and the impact of stress. A greater understanding of the regulation of the dopamine system and its disruption in schizophrenia may provide a more complete neurobiological framework to interpret clinical findings and develop novel treatments.

Keywords: amygdala; dopamine; hippocampus; medial septum; prefrontal cortex; thalamus; ventral tegmental area.

Figure 1

Tonic and phasic dopamine (DA) neuron activity are regulated by distinct afferent systems. DA neurons generate their own activity through a pacemaker conductance. However, a substantial population of DA neurons is not firing spontaneously, being held in a hyperpolarized state by a GABA-mediated inhibitory input from the ventral pallidum (VP). The VP, in turn, is controlled by a pathway originating from the ventral hippocampus (vHipp). The vHipp projects to the nucleus accumbens (NAc), which inhibits the VP. By contrast, phasic burst firing is driven by glutamatergic inputs arising from several areas, primary among these being the pedunculopontine tegmentum (PPTg). This afferent system regulates firing states within the population of spontaneously active DA neurons, because only neurons that are firing spontaneously can burst fire—NMDA channels on hyperpolarized (“silent”) DA neurons are under magnesium block and won't change state. Therefore, the PPTg provides the rapid, behaviorally salient phasic signal, whereas the VP, by controlling the number of DA neurons firing, determines the gain of the phasic signal.

Figure 2

The ventral hippocampus (vHipp) regulates midbrain DA system activity through a polysynaptic circuit. The vHipp excites neurons in the nucleus accumbens (NAc) that, in turn, inhibit ventral pallidal (VP) activity. Given that the VP provides an inhibitory tone to VTA DA neurons, activation of the vHipp results in an enhance VTA DA neuron activity. In schizophrenia, a PV+ interneuron cell loss combined with a disruption of corticothalamic projections contributes to the hyperactivity of glutamatergic pyramidal (Pyr) neurons in the vHipp that drives an increase in active DA neurons projecting to the associative striatum that underlies the emergence of psychotic symptoms in schizophrenia. NMDA receptor antagonists, such as PCP and ketamine, may similarly exacerbate or mimic psychosis by blocking NMDA receptors on PV+ interneurons and thus disinhibiting Pyr neurons. Corticothalamic-hippocampal abnormal interactions can induce a hyperdopaminergic state, for instance, through a dysfunction of the medial prefrontal cortex (mPFC) that could disinhibit the nucleus reuniens (RE), possibly via loss of feedforward inhibition from the reticular nucleus of the thalamus (TRN).