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 ( approximately 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 down-regulated by approximately 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.

Fig. 1.

Plot of Purkinje cell number from non-psychiatric subjects (NPS) (n = 24), schizophrenia (SZ) (n = 13) and bipolar (BP) disorder (n = 17) patients. In parentheses is the percentage of subjects with Purkinje cell number above and below cutoff point of 4.2. Note that 30.8% and 41.2% of the SZ and BP disorder patients had Purkinje neuron linear density ≥4.2 neurons/mm vs. 87.5% of NPS. To compare SZ vs. NPS, Fisher's exact test was used (P = 0.0008), whereas to compare BP vs. NPS, we used a chi-square test (P = 0.002).

Fig. 2.

Reelin mRNA in situ hybridization in human cerebellar cortex from an NPS (A), a SZ (B), and a BP disorder patient (C). Note the decrease of reelin mRNA signals in the granular cell layer (GCL) in SZ and BP disorder patients. Purkinje cells (PC) lack a reelin mRNA signal. (Scale bar: 10 μm.)

Fig. 3.

Plot of total Purkinje neuron number from wild-type mice (WTM) (n = 7) and heterozygous reeler mice (HRM) (n = 6). In parentheses is the percentage of mice with Purkinje cell number above and below cutoff point of 210 × 10³. Note that only 16.7% of HRM had Purkinje neuron density ≥210 × 10³ vs. 85.7% of WTM. To compare HRM vs. WTM, Fisher's exact test was used (P = 0.03).