Hippocampal circuit dysfunction in psychosis

Abstract

Despite strong evidence of the neurodevelopmental origins of psychosis, current pharmacological treatment is not usually initiated until after a clinical diagnosis is made, and is focussed on antagonising striatal dopamine receptors. These drugs are only partially effective, have serious side effects, fail to alleviate the negative and cognitive symptoms of the disorder, and are not useful as a preventive treatment. In recent years, attention has turned to upstream brain regions that regulate striatal dopamine function, such as the hippocampus. This review draws together these recent data to discuss why the hippocampus may be especially vulnerable in the pathophysiology of psychosis. First, we describe the neurodevelopmental trajectory of the hippocampus and its susceptibility to dysfunction, exploring this region's proneness to structural and functional imbalances, metabolic pressures, and oxidative stress. We then examine mechanisms of hippocampal dysfunction in psychosis and in individuals at high-risk for psychosis and discuss how and when hippocampal abnormalities may be targeted in these groups. We conclude with future directions for prospective studies to unlock the discovery of novel therapeutic strategies targeting hippocampal circuit imbalances to prevent or delay the onset of psychosis.

Fig. 1. Hippocampal subfield anatomy.

A The subdivisions of the hippocampus along its long axis—the dentate gyrus (DG) and four sections of the cornu ammonis (CA1 red; CA2, blue; CA3, green; CA4/DG, yellow; subiculum, cyan)—are demarcated early in prenatal neurodevelopment through specific genetic molecular markers. Segmentation derived from cytoarchitectonic anatomical probability map [244]. B Cross-section of left hippocampi, highlighting primary internal circuitry of the hippocampal formation. Solid lines reflect the ‘trisynaptic circuit’, dash lines reflect supporting entorhinal circuitry. Each subdivision of the hippocampus is linked to the neighbouring entorhinal cortex through the ‘trisynaptic circuit’, an excitatory projection that links hippocampal subregions via the perforant pathway to granule cells in the DG. These granule cells are linked to pyramidal cells in region CA3 via mossy fibres, which in turn project to pyramidal cells in CA1 via Schaffer collaterals, before exiting the hippocampus via the subiculum [245]. In addition to the trisynaptic circuit, there are supporting connections between the entorhinal cortex and CA1 and CA3, and subiculum, as well as projections between CA1 and CA3. The hippocampus receives input primarily from the entorhinal cortex but is also extensively connected with proximate regions, including the anterior cingulate (ACC), medial prefrontal cortex (mPFC), and amygdala [246]. The hippocampus sends direct outputs to the nucleus accumbens, hypothalamus, and thalamus, and indirect outputs to the striatum via the nucleus accumbens and ventral tegmental area [247].

Fig. 2. Model of hippocampal hyperactivity in early psychosis, highlighting potential targets for detection/intervention.

A Stressors lead to cascade of down-scale imbalances, including increased hippocampal metabolism and network (blue spheres) dysfunction (red spheres). Hub regions, including the hippocampus, are most likely to be impacted [43]. B Excitatory/inhibitory imbalance and hyperactivity in hippocampal subregions (enlarged arrows). C Oxidative stress damages metabolically demanding parvalbumin-positive interneurons (PVI), resulting in N-methyl-D-aspartate receptor (NMDAR) hypofunction and (1) altered pyramidal signalling; (2) reduced pyramidal input to interneurons; (3) reduced interneuron inhibition of pyramidal cells, and a cascade of up-scale imbalances These processes are accentuated in those at highest genetic risk. Diagram adapted in part, with permission [248].

Fig. 3. Prototypical psychosis developmental timeline with suggested periods for targeted interventions to alter psychosis trajectory.

Individuals at higher risk could be identified through normative modelling [232] at different neurodevelopmental timepoints (A). Modelling may include a regional vulnerability index [50] or other hippocampal markers (Table 1). Personalised treatments could then be tailored to specific anomalies.