Developmental pathology, dopamine, stress and schizophrenia

Abstract

Psychological stress is a contributing factor for a wide variety of neuropsychiatric diseases including substance use disorders, anxiety, depression and schizophrenia. However, it has not been conclusively determined how stress augments the symptoms of these diseases. Here we review evidence that the ventral hippocampus may be a site of convergence whereby a number of seemingly discrete risk factors, including stress, may interact to precipitate psychosis in schizophrenia. Specifically, aberrant hippocampal activity has been demonstrated to underlie both the elevated dopamine neuron activity and associated behavioral hyperactivity to dopamine agonists in a verified animal model of schizophrenia. In addition, stress, psychostimulant drug use, prenatal infection and select genetic polymorphisms all appear to augment ventral hippocampal function that may therefore exaggerate or precipitate psychotic symptoms. Such information is critical for our understanding into the pathology of psychiatric disease with the ultimate aim being the development of more effective therapeutics.

Figure 1

Ventral hippocampal (vHipp) regulation of dopamine neuron activity in normal and diseased states. (left) In the normal individual, the vHipp regulates the number of spontaneously active dopamine neurons in the VTA via a multisynaptic pathway. Therefore, low levels of activity in the non-stimulated condition lead to low levels of glutamatergic drive (red arrow) of GABAergic neurons in the accumbens (Acb). As a result, there is a low level of inhibition of GABAergic neurons in the ventral pallidum (VP, black arrow). The VP, in turn, produces a potent inhibition of DA neuron firing (black arrow), allowing only a small proportion of VTA dopamine neurons to fire spontaneously. (right) In schizophrenia, aberrant high levels of vHipp activity causes the Acb to potently inhibit the VP, thereby dramatically increasing the number of spontaneously active dopamine neurons in the VTA

Figure 2

The ventral hippocampus represents a site of convergence by which distinct risk factors can regulate limbic system function. Thus, hippocampal pathology, driven by genetic and environmental factors, is likely to be exacerbated by stress or substance abuse. This aberrant vHipp activity augments dopamine transmission leading to psychosis.