Hippocampus and memory abnormalities in schizophrenia: contributions of genes and environment

Abstract

Schizophrenia is an etiologically complex and severely debilitating psychiatric syndrome. The search for etiological factors and their mode of action in complex diseases requires an approach that allows for the assessment of disease liability irrespective of diagnosis. This thesis comprises a series of studies, employing epidemiologically valid samples, to examine genetic and environmental influences on hippocampal morphology, assessed using magnetic resonance imaging, and verbal declarative memory, assessed with the California Verbal Learning Test. The first study explored the contributions of genetic predisposition and history of fetal hypoxia to hippocampal volume in patients with psychosis using a family design. Patients had smaller hippocampal volumes than their full-siblings, who had smaller hippocampal volumes than healthy individuals. Only among patients, smaller hippocampal volumes were observed in those who experienced fetal hypoxia compared with those who did not. These findings suggest that in patients with schizophrenia spectrum disorders, hippocampal volume is influenced in part by schizophrenia susceptibility genes and in part by an interaction of these genes with fetal hypoxia. The second study employed a twin design to establish whether the familial effect on reduced hippocampal volume in study one represents a genetic vulnerability marker for schizophrenia. Patients from dizygotic but not monozygotic pairs had smaller left hippocampi compared with their non-ill co-twins. Further, unaffected monozygotic, but not dizygotic, co-twins exhibited smaller left hippocampi compared with control twins. These findings suggest genetic influences on hippocampal volume reduction in schizophrenia. The third study, which employed an extended twin sample, found smaller hippocampi in patients compared with their non-ill monozygotic and dizygotic co-twins and healthy twins. Moreover, hippocampi of patients' non-ill co-twins were smaller than those of healthy twins. Heritability estimates for hippocampal volumes were seventy-one percent in healthy twins and forty-two percent in twins discordant for schizophrenia. These findings indicate that hippocampal volumes in healthy individuals are largely influenced by genetic factors, and subject to substantially greater modulation by environmental factors in schizophrenia. Given the putative involvement of the hippocampus in explicit memory, study four examined the sources of verbal recall and recognition deficits in schizophrenia. Compared with controls, patients and their co-twins showed relatively greater performance deficits on free recall compared with recognition. Both on free recall and recognition patients remembered fewer words than their monozygotic co-twins. The intra-pair differences between patients and their non-ill co-twins in hippocampal volume and memory performance were highly positively correlated. These findings suggest that genetic influences are associated with reduced verbal recall in schizophrenia, but that non-genetic influences further compromise these abnormalities in patients who manifest the full-blown schizophrenia phenotype, with this additional degree of disease-related declarative memory deficit mediated in part by hippocampal pathology. In conclusion, this thesis provides robust evidence for genetic and environmental influences on hippocampal morphological and verbal declarative memory abnormalities in schizophrenia, but much work lies ahead in order to determine the specific timing of occurrence of these deficits, the underlying micro-anatomical and molecular genetic bases, and their role in the expression of the symptoms that characterize the schizophrenia syndrome