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.

Evidence for impaired hippocampal circuitry in schizophrenia and its link to memory dysfunction

“…Our analysis revealed a relationship between our behavioral memory measures and PSYRAT delusions score, but not the hallucination score, consistent with our hypothesis. These findings support a link between memory dysfunction and delusions in schizophrenia and provide evidence for theories that suggest delusions are particularly linked to aberrant memories 39 and that memory system dysfunction contributes to psychosis 3,14 .…”

“…Individuals with schizophrenia exhibit deficits in relational memory 5,6 and item recollection 7,8 , may form fixed false memories 9 (associated with delusions 10 ), and are impaired in mnemonic discrimination of highly similar events 11,12 . Accordingly, several lines of evidence point to the hippocampus as a critical region affected by the disorder 3,13 , strengthening the hypothesis that hippocampal dysfunction may play a role in the pathophysiology of schizophrenia 1,2,3,14 . There has been consistent evidence for hippocampal volume reduction 13,15,16 prominent in the early stages of the illness 17 , which is more pronounced than reductions in other brain structures 18 .…”

“…Imaging data were obtained using a 3T Siemens Skyra scanner with a 32-channel head coil at Suzhou Guangji Hospital imaging center. Anatomical images were collected using T1 and T2 weighted protocols (1mm 3 resolution). Both T1 and T2 images were obtained from 57 participants (28 patients and 29 controls) and only T1 images from 37 participants (17 patients and 20 controls), due to technical issues that delayed the acquisition of T2 images at the beginning of the data collection period.…”

Increased Hippocampal Blood Flow in People at Clinical High Risk for Psychosis and Effects of Cannabidiol

“…The molecular mechanisms by which CBD might have its effects on hippocampal rCBF remain unclear (Pertwee, 2008), but preclinical and in vitro work suggests that the general effects of CBD may be mediated by various mechanisms, including negative allosteric modulation of the CB1 receptor (Laprairie et al ., 2015). CB1 is highly expressed in hippocampus (Glass et al ., 1997) and CB1 agonism has been shown to disinhibit glutamatergic pyramidal neurons (Hájos et al ., 2000), an effect directly related to circuit-based models of psychosis (Fig S1) and which may be predicted to increase hippocampal blood flow (Lisman et al ., 2008; Knight et al ., 2022). By ‘antagonising the agonists’ of CB1 and impacting hippocampal endocannabinoid tone, it is possible that CBD modulates CBF through these direct receptor/circuit mechanisms.…”

“…Such individuals are said to be at Clinical High Risk for psychosis (CHR) and have a ∼20% three-year risk of transitioning to the full-blown disorder (Fusar-Poli et al ., 2020a). The neurobiological mechanisms underlying psychosis onset are incompletely understood (Millan et al ., 2016), but compelling evidence places hippocampal dysfunction at the centre of its pathophysiology (Tamminga et al ., 2010; Lieberman et al ., 2018; Knight et al ., 2022). Specifically, preclinical models suggest that hippocampal hyperactivity is key to the development of psychosis and arises due to NMDA receptor hypofunction on GABAergic interneurons, leading to disinhibition of hippocampal pyramidal cells (Lodge and Grace, 2007; Lisman et al ., 2008) (Supplementary Fig S1).…”