Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression

Abstract

Accumulation of neurobiological knowledge points to neurodevelopmental origins for certain psychotic and mood disorders. Recent landmark postmortem reports implicate Reelin, a secretory glycoprotein responsible for normal lamination of brain, in the pathology of schizophrenia and bipolar disorders. We employed quantitative immunocytochemistry to measure levels of Reelin protein in various compartments of hippocampal formation in subjects diagnosed with schizophrenia, bipolar disorder and major depression compared to normal controls. Significant reductions were observed in Reelin-positive adjusted cell densities in the dentate molecular layer (ANOVA, P Ͻ 0.001), CA4 area (ANOVA, P Ͻ 0.001), total hippocampal area (ANOVA, P Ͻ 0.038) and in Reelin-positive cell counts in CA4 (ANOVA, P Ͻ 0.042) of schizophrenics vs controls. Adjusted Reelin-positive cell densities were also reduced in CA4 areas of subjects with bipolar disorder (ANOVA, P Ͻ 0.001) and nonsignificantly in those with major depression. CA4 areas were also significantly reduced in schizophrenic (ANOVA, P Ͻ 0.009) patients. No significant effects of confounding variables were found. The exception was that family history of psychiatric illness correlated strongly with Reelin reductions in several areas of hippocampus (CA4, adjusted cell density, F = 13.77, P = 0.001). We present new immunocytochemical evidence showing reductions in Reelin expression in hippocampus of subjects with schizophrenia, bipolar disorder and major depression and confirm recent reports documenting a similar deficit involving Reelin expression in brains of subjects with schizophrenia and bipolar disorder. Molecular Psychiatry (2000) 5, 654-663.

Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network

“…The same group reported reduced reelin levels in cerebellar tissue from five individuals with autism relative to levels in controls [Fatemi et al, 2001b]. This latter finding may not be specific to autism as reduced reelin protein levels have also been reported in cerebellar and other brain regions in schizophrenia, bipolar disorder, and major depression [Impagnatiello et al, 1998;Fatemi et al, 2000Fatemi et al, , 2001aGuidotti et al, 2000]. Finally, in humans, null mutations in RELN cause an autosomal recessive form of lissencephaly, a severe brain developmental disorder.…”

Reelin glycoprotein: structure, biology and roles in health and disease

“…Reduction in Reelin was associated with significant decreases in Glutamic acid decarboxylase 67 kDa protein, in the same postmortem brains. 59 A later immunocytochemical report, 52 showed significant reductions in Reelin immunoreactivity in schizophrenic and bipolar patients. However, these authors detected similar decreases in hippocampal Reelin protein levels in non-psychotic bipolar and depressed subjects, suggesting that Reelin deficiency may not be limited to subjects with psychosis alone.…”

“…However, these authors detected similar decreases in hippocampal Reelin protein levels in non-psychotic bipolar and depressed subjects, suggesting that Reelin deficiency may not be limited to subjects with psychosis alone. 52 Fatemi et al subsequently demonstrated significant reductions in Reelin as well as GAD65 and 67 kDa proteins in cerebella of subjects with schizophrenia, bipolar disorder and major depression. 60 Further confirmatory data relating to Reelin abnormalities, in brains of schizophrenic patients, were demonstrated by Eastwood et al, 61 who showed a trend for reduction in Reelin mRNA in cerebella of schizophrenic subjects; these reductions in Reelin mRNA correlated negatively with semaphorin 3A.…”

“…2 In the adult mammalian brain, Reelin is localized to layer I cortical Cajal-Retzius cells, cortical GABAergic interneurons in layers II-IV, 50 cerebellar granule cells 51 and hippocampal interneurons. 52 Presence of Reelin-positive cells in the adult hippocampus indicates that Reelin function is not restricted to embryonic period, but may continue throughout adult life. 53 While controversial, a recent report demonstrates coexpression of Reelin and Dab-1 in Cajal-Retzius cells during cortical development, and in cortical pyramidal cells in the adult CNS.…”

“…Moreover, Reelin is largely replaced by Reelinexpressing GABAergic interneurons that are dispersed throughout the mammalian neocortex 50 and hippocampus. 52,53 Levels of the Reelin receptors ApoER2, VLDLR and a3b1 integrin and the adapter protein Dab-1, which are all essential to the Reelin signaling system, remain expressed in adult brain. 53 Previous work by Rodriguez et al 19 showed an association between Reelin and its receptor a3b1 integrin with synaptic structures, raising the possibility of a potential role in neurotransmission.…”