Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia

Abstract

Substantial evidence suggests that psychosis in schizophrenia is associated with dysregulation of subcortical dopamine system function. Here we examine evidence that this dysregulation is secondary to hyperactivity within hippocampal subfields. Enhanced hippocampal activity has been reported in preclinical models and in schizophrenia patients. Moreover, this hippocampal hyperactivity is correlated with enhanced dopamine neuron activity and positive symptoms, respectively. Thus, restoration of hippocampal function could provide a more effective therapeutic approach than current therapeutics based on blockade of dopamine D2 receptors. Indeed, initial studies demonstrate that allosteric modulation of the α5GABA(A) receptor can decrease aberrant dopamine signaling and associated behaviors in a verified rodent model of psychosis.

Figure 1

The ventral hippocampus (vHipp) regulates dopamine neuron activity via a polysynaptic projection. Thus, the vHipp excites neurons in the nucleus accumbens that, in turn, inhibit ventral pallidal (VP) activity. Given that the VP provides an inhibitory tone to the dopamine neurons of the VTA, activation of the vHipp will result in an increase dopamine neuron activity. In schizophrenia, hippocampal activity is pathologically enhanced which leads to an enduring increase in dopamine system function. Adapted from [64].

Figure 2

Under normal (non-pathological) conditions, the number of dopamine neurons spontaneously active can be modulated to permit an appropriate behavioral response based on the environmental setting. In schizophrenia, the dopamine neuron population activity is pathologically in a constant high-activity state and, as such, all stimuli the organism encounters will lead to maximal dopamine output, resulting in the attribution of strong behavioral importance to stimuli, even to stimuli that should be safely ignored. Conventional antipsychotics decrease dopamine neuron activity via depolarization block; this would decrease the salience of all encountered stimuli but fails to restore the flexibility of the system. Novel therapeutics aimed at normalizing hippocampal function, i.e. allosteric modulators of the α5GABA_A receptor, restores normal dopamine function by acting upstream at the proposed site of pathology.

Figure 3

The alpha 5 subunit is discretely distributed with high levels of expression limited to the hippocampus. These receptors are primarily extrasynaptic, localized to the base of the dendritic spines of pyramidal neurons. Thus, the α5-GABA_A receptor is positioned to be activated by synaptic GABA (dark circles) as well as ‘spillover’ from adjacent synapses to provide an inhibitory input to glutamatergic hippocampal projection neurons. SH-053-2′F-R-CH₃ (blue stars) binds to an allosteric, benzodiazepine site of the α5-GABA_A receptor, and augments the endogenous inhibition of the pyramidal neuron.