Lower number of cerebellar Purkinje neurons in psychosis is associated with reduced reelin expression

Abstract

Reelin is an extracellular matrix protein synthesized in cerebellar granule cells that plays an important role in Purkinje cell positioning during cerebellar development and in modulating adult synaptic function. In the cerebellum of schizophrenia (SZ) and bipolar (BP) disorder patients, there is a marked decrease (≈50%) of reelin expression. In this study we measured Purkinje neuron density in the Purkinje cell layer of cerebella of 13 SZ and 17 BP disorder patients from the McLean 66 Cohort Collection, Harvard Brain Tissue Resource Center. The mean number of Purkinje neurons (linear density, neurons per millimeter) was 20% lower in SZ and BP disorder patients compared with nonpsychiatric subjects (NPS; n = 24). This decrease of Purkinje neuron linear density was unrelated to postmortem interval, pH, drugs of abuse, or to the presence, dose, or duration of antipsychotic medications. A comparative study in the cerebella of heterozygous reeler mice (HRM), in which reelin expression is downregulated by ≈50%, showed a significant loss in the number of Purkinje cells in HRM (10-15%) compared with age-matched (3-9 months) wild-type mice. This finding suggests that lack of reelin impairs GABAergic Purkinje neuron expression and/or positioning during cerebellar development.A number of behavioral, neuropathologic, neuroimaging, and neurochemical studies suggest that the cerebellum may be defective in schizophrenia (SZ) (for a review see ref. 1). We (2, 3) and others (4) have reported that cerebella from SZ and bipolar (BP) disorder patients exhibit a 50% decrease in the expression of glutamic acid decarboxylase 67 (GAD67), which is a major GABA synthesizing enzyme present in cerebellar Purkinje neurons. This decrease suggests that these GABAergic principal neurons may be damaged. We also reported that in the cerebellar glutamatergic granule cells of SZ and BP disorder patients, there is a marked decrease of reelin mRNA levels (2, 3).A decrease of reelin levels in the cerebellum of SZ patients has been confirmed in other studies (4). In addition, the reduction of reelin mRNA is negatively correlated with the expression of the transcription factor semaphorin 3A in the cerebella of subjects with SZ (5).Reelin is a large (≈400 kDa) extracellular matrix protein synthesized by GABAergic interneurons in the telencephalon and by glutamatergic granule cells in the cerebellum (6-9). It is secreted extracellularly by constitutive mechanisms (10) and is believed to play a significant role in glutamate receptor homeostasis and spine formation in the adult brain (11)(12)(13)(14).The heterozygous reeler mouse (HRM), which expresses ≈50% of the amount of reelin present in brains of wild-type mice (WTM), displays certain behavioral and anatomic abnormalities reminiscent of those found in SZ patients. These include (i) prepulse inhibition deficits, which are a measure of sensory motor gating of the CNS (15), (ii) contextual fear conditioning deficits, which are a measure of a hippocampal/amygdaladependent function (16), and (iii) long-te...

Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration

“…Interestingly, Maloku et al (2010) have also found a similar PC loss in adult reelin-haploinsufficient mice, and have interpreted their findings in the context of reelin deficiency and cerebellar abnormalities observed in schizophrenia, thus underscoring the links between reelin and psychosis. The question why reelin haploinsufficiency leads to cell loss in the male but not in the female cerebellum, and how high levels of estradiol at P5 inhibit cell loss, cannot be answered yet, but recent data indicate that PCs show a peak of apoptosis during the first postnatal week in the mouse (Jankowski et al, 2009).…”

Steroid sulfatase is a potential modifier of cognition in Attention Deficit Hyperactivity Disorder

“…By extension, altered STS expression is likely to adversely affect the development of these structures. Hence, high levels of STS expression in the thalamus, basal ganglia and cerebellar neuroepithelium (which gives rise to GABAergic and glutamatergic neurons of the cerebellum; Hoshino et al 2005) were of particular interest, given prior data suggesting aberrant development of these regions in both ADHD (Dickstein et al 2006;Perlov et al 2009;Silk et al 2009;Valera et al 2007) and schizophrenia (Ellison-Wright & Bullmore 2010;Maloku et al 2010). Similarly, altered STS function in the hypothalamus/pituitary gland, olfactory epithelium and tongue could feasibly play a role in the altered hypothalamic-pituitary-adrenal axis responsivity (van West et al 2009), odor detection abnormalities (Karsz et al 2008;Romanos et al 2008) and tongue characteristics (Atmetlla et al 2006) previously described in ADHD.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…RELN is expressed in Cajal-Retzius cells during early development and from many GABAergic cells in multiple cortical layers shortly after birth (Alcantara et al, 2006). Brain tissue from schizophrenic patients also consistently report decreased expression of the RELN gene Fatemi et al, 2000Fatemi et al, , 2001Folsom and Fatemi, 2013;Guidotti et al, 2000a;Habl et al, 2012;Impagnatiello et al, 1998;Maloku et al, 2010;Ruzicka et al, 2007), which is likely the result of altered genetic and/ or epigenetic regulation (Costa et al, 2003;Grayson et al, 2005Grayson et al, , 2006Tochigi et al, 2008;Veldic et al, 2004Veldic et al, , 2007. While the RELN deficiency observed in post-mortem tissue clearly does not impact cortical architecture to the same degree as total RELN loss during cortical development, it is likely that even a small reduction of RELN would affect synaptic integration during development and/or synaptic stability and plasticity in adulthood (Frotscher, 2010).…”

“…In addition to being a necessary component of cortical development, RELN also has a role in stabilizing neurons and synapses throughout life (Abraham and Meyer, 2003;Frotscher, 2010;Guidotti et al, 2000b). It is expressed by GABAergic interneurons and the expression of the GAD1 and RELN genes is tightly coordinated by a common epigenetic mechanism (Costa et al, 2004;Grayson et al, 2005Grayson et al, , 2006Guidotti et al, 2000a;Impagnatiello et al, 1998;Kundakovic et al, 2009;Maloku et al, 2010;Noh et al, 2005;Pesold et al, 1999;Rodriguez et al, 2002;Ruzicka et al, 2007;Tochigi et al, 2008;Veldic et al, 2004Veldic et al, , 2007. In addition, rodent models show that RELN deficiency alone can result in downstream reductions of both GAD1 (Kutiyanawalla et al, 2012;Nullmeier et al, 2011;Pascual et al, 2004;Takayama, 1994) and BDNF (Pillai and Mahadik, 2008).…”