Hippocampal volume and hippocampal neuron density, number and size in schizophrenia: a systematic review and meta-analysis of postmortem studies

Abstract

Reduced hippocampal volume is a consistent finding in neuroimaging studies of individuals with schizophrenia. While these studies have the advantage of large sample sizes, they are unable to quantify the cellular basis of structural or functional changes. In contrast, postmortem studies are well suited to explore subfield and cellular alterations, but low sample sizes and subject heterogeneity impede establishment of statistically significant differences. Here we use a meta-analytic approach to synthesize the extant literature of hippocampal subfield volume and cellular composition in schizophrenia patients and healthy control subjects. Following pre-registration (PROSPERO CRD42019138280), PubMed, Web of Science, and PsycINFO were searched using the term: (schizophrenia OR schizoaffective) AND (post-mortem OR postmortem) AND hippocampus. Subjects were adult men and women with schizophrenia or schizoaffective disorder or non-psychiatric control subjects, and key outcomes, stratified by hippocampal hemisphere and subfield, were volume, neuron number, neuron density, and neuron size. A random effects meta-analysis was performed. Thirty-two studies were included (413 patients, 415 controls). In patients, volume and neuron number were significantly reduced in multiple hippocampal subfields in left, but not right hippocampus, whereas neuron density was not significantly different in any hippocampal subfield. Neuron size, averaged bilaterally, was also significantly reduced in all calculated subfields. Heterogeneity was minimal to moderate, with rare evidence of publication bias. Meta-regression of age and illness duration did not explain heterogeneity of total hippocampal volume effect sizes. These results extend neuroimaging findings of smaller hippocampal volume in schizophrenia patients and further our understanding of regional and cellular neuropathology in schizophrenia.

Modeling intrahippocampal effects of anterior hippocampal hyperactivity relevant to schizophrenia using chemogenetic excitation of long axis-projecting mossy cells in the mouse dentate gyrus

“…The present results, along with post-mortem evidence for cellular and biochemical changes in human hippocampal area CA4 (75-77) support future investigation into vMC function in rodent models for ventral hippocampal hyperactivation and cognitive deficits seen in schizophrenia. A key goal is to determine why vMC inhibition or excitation impairs spatial encoding.…”

Cannabidiol modulation of hippocampal glutamate in early psychosis

“…Previous research has demonstrated that the hippocampus is a key substrate for pathophysiological alterations in psychosis ( Allen et al, 2016 ; Cao and Cannon, 2020 ; Lieberman et al, 2018 ; Lodge and Grace, 2011 ; McHugo et al, 2019 ; Schobel et al, 2013 ; Vargas et al, 2018 ). Independent evidence also suggests that cellular neuropathology may be evident in the left rather than right hippocampus in schizophrenia ( Roeske et al, 2020 ). As such, previous magnetic resonance spectroscopy (MRS) studies have commonly acquired data from the left hippocampus ( Bossong et al, 2019 ; Briend et al, 2020 ; Merritt et al, 2016 ; Shakory et al, 2018 ).…”

Developmental Characterization of Schizophrenia-Associated Gene Zswim6 in Mouse Forebrain

“…Strong Zswim6 expression is detected in the CA1 and CA3 of the hippocampus. The hippocampus is known to be involved in the pathogenesis of schizophrenia (Ho et al, 2017;Roeske et al, 2020). Interestingly, Zswim6 is expressed in the medial habenula in which the schizophrenia-risk gene ErbB4 is also highly expressed (Steiner et al, 1999).…”