Emerging therapeutic targets for schizophrenia: a framework for novel treatment strategies for psychosis

Abstract

Introduction: Antipsychotic drugs are central to the treatment of schizophrenia, but their limitations necessitate improved treatment strategies. Multiple lines of research have implicated glutamatergic dysfunction in the hippocampus as an early source of pathophysiology in schizophrenia. Novel compounds have been designed to treat glutamatergic dysfunction, but they have produced inconsistent results in clinical trials. Areas covered: This review discusses how the hippocampus is thought to drive psychotic symptoms through its influence on the dopamine system. It offers the reader an evaluation of proposed treatment strategies including direct modulation of GABA or glutamate neurotransmission or reducing the deleterious impact of stress on circuit development. Finally, we offer a perspective on aspects of future research that will advance our knowledge and may create new therapeutic opportunities. PubMed was searched for relevant literature between 2010 and 2020 and related studies. Expert opinion: Targeting aberrant excitatory-inhibitory neurotransmission in the hippocampus and its related circuits has the potential to alleviate symptoms and reduce the risk of transition to psychosis if implemented as an early intervention. Longitudinal multimodal brain imaging combined with mechanistic theories generated from animal models can be used to better understand the progression of hippocampal-dopamine circuit dysfunction and heterogeneity in treatment response.

Keywords: Schizophrenia; antipsychotic; d2; dopamine; early intervention; gaba; glutamate; hippocampus.

Figure 1.. The hippocampus regulates DA neuron population activity through a polysynaptic circuit.

Pyramidal neurons (Pyr) in the subiculum of the hippocampus send excitatory projections to neurons in the nucleus accumbens that, in turn, inhibit activity in the ventral pallidum. The ventral pallidum holds a variable subset of DA neurons in the ventral tegmental area (VTA) in an inhibited state. Through this circuit, activation of the hippocampus modulates the number of spontaneously active DA neurons. In schizophrenia, hyperactivity of Pyr in the hippocampus, following a loss of PV+ interneurons, drives an increase in DA neuron population activity. The increased gain results in increased phasic striatal DA release.