Gene expression profile associated with postnatal development of pyramidal neurons in the human prefrontal cortex implicates ubiquitin ligase E3 in the pathophysiology of schizophrenia onset

Abstract

Schizophrenia is a neurodevelopmental disorder with the typical age of onset of overt symptoms and deficits occurring during late adolescence or early adulthood, coinciding with the final maturation of the cortical network involving the prefrontal cortex. These observations have led to the hypothesis that disturbances of the developmental events that take place in the prefrontal cortex during this period, specifically the remodeling of synaptic connectivities between pyramidal neurons, may contribute to the onset of illness. In this context, we investigated the gene expression changes of pyramidal neurons in the human prefrontal cortex during normal periadolescent development in order to gain insight into the possible molecular mechanisms involved in synaptic remodeling of pyramidal neuronal circuitry. Our data suggest that genes associated with the ubiquitination system, which has been implicated in the biology of synaptic plasticity, may play a major role. Among these genes, UBE3B, which encodes the ubiquitin ligase E3, was found to undergo periadolescent increase and was validated at the protein level to be upregulated during periadolescent development. Furthermore, we found that the density of UBE3B-immunoreactive pyramidal neurons was decreased in schizophrenia subjects, consistent with the result of a previous study of decreased UBE3B mRNA expression in pyramidal neurons in this illness. Altogether these findings point to the novel hypothesis that this specific ligase may play a role in the developmental pathogenesis of schizophrenia onset by possibly altering the synaptic remodeling process.

Keywords: Adolescence; Prefrontal cortex; Schizophrenia; Synaptic pruning; Ubiquitin ligase.

Figure 1

A. Principal component analysis reveals the segregation of the data into two age groups. Note that the purple and orange circles correspond to cases PFC2-8 and PFC9-14 shown in Table 1, respectively. B. Differentially expressed genes visualized by unsupervised hierarchical clustering based on the stringency criteria of FC=1.5 and p=0.05.

Figure 2

Expression levels of two highly differentially expressed genes and three randomly selected genes as determined by microarray and qRT-PCR were significantly correlated (R=0.86, p=0.001).

Figure 3

The density of UBE3B-immunoreactive cells in the prefrontal cortex progressively increases during postnatal development. Scale bar=100 μm.

Figure 4

Photomicrograph showing a pyramidal neuron (labeled with SMI32) that expresses UBE3B. UBE3B is also localized to other cell types, including nonpyramidal neurons and possibly glia. Scale bar=25 μm. Densities of UBE3B-immunoreactive cells (B) and UBE3B-immunoreactive pyramidal cells (B) are significantly decreased by 22.3 % (p=0.026) and 48.0% (p=0.022), respectively, in schizophrenia (1,483±437/mm² and 594±328/mm², respectively) compared to normal control (1,909±546/mm² and 1,136±364/mm², respectively) subjects. These findings were not affected by any of the potential confounding variables including age, PMI, and antipsychotic medications (Supplementary Table S14).