Transcriptomic immaturity of the hippocampus and prefrontal cortex in patients with alcoholism

Tomoyuki Murano,Tsuyoshi Miyakawa,Hisatsugu Koshimizu,Hideo Hagihara

doi:10.1038/srep44531

Abstract

Alcoholism, which is defined as the recurring harmful use of alcohol despite its negative consequences, has a lifetime prevalence of 17.8%. Previous studies have shown that chronic alcohol consumption disrupts various brain functions and behaviours. However, the precise mechanisms that underlie alcoholism are currently unclear. Recently, we discovered “pseudo-immature” brain cell states of the dentate gyrus and prefrontal cortex (PFC) in mouse models of psychotic disorders and epileptic seizure. Similar pseudo-immaturity has been observed in patients with psychotic disorders, such as schizophrenia and bipolar disorder. Patients with alcoholism occasionally exhibit similar psychological symptoms, implying shared molecular and cellular mechanisms between these diseases. Here, we performed a meta-analysis to compare microarray data from the hippocampi/PFCs of the patients with alcoholism to data from these regions in developing human brains and mouse developmental data for specific cell types. We identified immature-like gene expression patterns in post-mortem hippocampi/PFCs of alcoholic patients and the dominant contributions of fast-spiking (FS) neurons to their pseudo-immaturity. These results suggested that FS neuron dysfunction and the subsequent imbalance between excitation and inhibition can be associated with pseudo-immaturity in alcoholism. These immaturities in the hippocampi/PFCs and the underlying mechanisms may explain the psychotic symptom generation and pathophysiology of alcoholism.

Highlights

GPL5175 Affymetrix Human Exon 1.0 ST Array [transcript version] GPL5188 Affymetrix Human Exon 1.0 ST Array [probe set version]
We found that the gene expression patterns in the hippocampi of the male patients with alcoholism and the typically developing controls strongly overlapped
42 probes were up-regulated in the infant group but down-regulated in the patient group (P = 0.1089; Fig. 2b), whereas 23 probes were down-regulated in the infant group but up-regulated in the patient group (P = 1.5 × 10−5; Fig. 2b). These results indicated that the gene expression patterns in the prefrontal cortices (PFC) of the male alcoholic patients were highly similar to the patterns in the PFCs of the infants

Summary

Introduction

GPL5175 Affymetrix Human Exon 1.0 ST Array [transcript (gene) version] GPL5188 Affymetrix Human Exon 1.0 ST Array [probe set (exon) version]. Detected transcriptomic immaturity in the prefrontal cortices (PFC) of patients with schizophrenia[6,12] These immature-like neuronal states appear to exist in various brain areas of patients with psychotic disorders. Other studies showed that parvalbumin-positive neurons were damaged and decreased and GFAP-positive cells were increased in an animal model of alcohol abuse[14,15]. These molecular marker pattern changes are somewhat similar to the pattern changes observed in mice exhibiting iDG, which suggests that the hippocampus and PFC of ethanol-treated mice may share common transcriptional properties with the immature hippocampus and PFC in normal healthy infants. The overlap between gene sets and the directional information for each gene were examined

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