The gene expression patterns as surrogate indices of pH in the brain.

Hydrogen ion (H+) is one of the most potent intrinsic neuromodulators in the brain in terms of concentration. Changes in H+ concentration, expressed as pH, are thought to be associated with various biological processes, such as gene expression, in the brain. Accumulating evidence suggests that decreased brain pH is a common feature of several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and Alzheimer's disease. However, it remains unclear whether gene expression patterns can be used as surrogates for pH changes in the brain. In this study, we performed meta-analyses using publicly available gene expression datasets to profile the expression patterns of pH-associated genes, whose expression levels were correlated with brain pH, in human patients and mouse models of major central nervous system (CNS) diseases, as well as in mouse cell-type datasets. Comprehensive analysis of 281 human datasets from 11 CNS disorders revealed that gene expression associated with decreased pH was over-represented in disorders including schizophrenia, bipolar disorder, autism spectrum disorders, Alzheimer's disease, Huntington's disease, Parkinson's disease, and brain tumors. Expression patterns of pH-associated genes in mouse models of neurodegenerative disease showed a common time course trend toward lower pH over time. Furthermore, cell type analysis identified astrocytes as the cell type with the most acidity-related gene expression, consistent with previous experimental measurements showing a lower intracellular pH in astrocytes than in neurons. These results suggest that the expression pattern of pH-associated genes may be a surrogate for the state- and trait-related changes in pH in brain cells. Altered expression of pH-associated genes may serve as a novel molecular mechanism for a more complete understanding of the transdiagnostic pathophysiology of neuropsychiatric and neurodegenerative disorders.

Multiple types of navigational information are independently encoded in the population activities of the dentate gyrus neurons.

The dentate gyrus (DG) plays critical roles in cognitive functions, such as learning, memory, and spatial coding, and its dysfunction is implicated in various neuropsychiatric disorders. However, it remains largely unknown how information is represented in this region. Here, we recorded neuronal activity in the DG using Ca2+ imaging in freely moving mice and analyzed this activity using machine learning. The activity patterns of populations of DG neurons enabled us to successfully decode position, speed, and motion direction in an open field, as well as current and future location in a T-maze, and each individual neuron was diversely and independently tuned to these multiple information types. Our data also showed that each type of information is unevenly distributed in groups of DG neurons, and different types of information are independently encoded in overlapping, but different, populations of neurons. In alpha-calcium/calmodulin-dependent kinase II (αCaMKII) heterozygous knockout mice, which present deficits in spatial remote and working memory, the decoding accuracy of position in the open field and future location in the T-maze were selectively reduced. These results suggest that multiple types of information are independently distributed in DG neurons.

Expression of progenitor cell/immature neuron markers does not present definitive evidence for adult neurogenesis.

It is agreed upon that adult hippocampal neurogenesis (AHN) occurs in the dentate gyrus (DG) in rodents. However, the existence of AHN in humans, particularly in elderly individuals, remains to be determined. Recently, several studies reported that neural progenitor cells, neuroblasts, and immature neurons were detected in the hippocampus of elderly humans, based on the expressions of putative markers for these cells, claiming that this provides evidence of the persistence of AHN in humans. Herein, we briefly overview the phenomenon that we call "dematuration," in which mature neurons dedifferentiate to a pseudo-immature status and re-express the molecular markers of neural progenitor cells and immature neurons. Various conditions can easily induce dematuration, such as inflammation and hyper-excitation of neurons, and therefore, the markers for neural progenitor cells and immature neurons may not necessarily serve as markers for AHN. Thus, the aforementioned studies have not presented definitive evidence for the persistence of hippocampal neurogenesis throughout adult life in humans, and we would like to emphasize that those markers should be used cautiously when presented as evidence for AHN. Increasing AHN has been considered as a therapeutic target for Alzheimer's disease (AD); however, given that immature neuronal markers can be re-expressed in mature adult neurons, independent of AHN, in various disease conditions including AD, strategies to increase the expression of these markers in the DG may be ineffective or may worsen the symptoms of such diseases.

Erratum: Author Correction: Transcriptomic immaturity inducible by neural hyperexcitation is shared by multiple neuropsychiatric disorders.

[This corrects the article DOI: 10.1038/s42003-018-0277-2.].

Transcriptomic immaturity inducible by neural hyperexcitation is shared by multiple neuropsychiatric disorders.

Biomarkers are needed to improve the diagnosis of neuropsychiatric disorders, which are often associated to excitatory/inhibitory imbalances in neural transmission and abnormal maturation. Here, we characterized different disease conditions by mapping changes in the expression patterns of maturation-related genes whose expression was altered by experimental neural hyperexcitation in published studies. This analysis revealed two gene expression patterns: decreases in maturity markers and increases in immaturity markers. These two groups of genes were characterized by the over-representation of genes related to synaptic function and chromosomal modification, respectively. Using these two groups in a transdiagnostic analysis of 87 disease datasets for eight neuropsychiatric disorders and 12 datasets from corresponding animal models, we found that transcriptomic pseudoimmaturity inducible by neural hyperexcitation is shared by multiple neuropsychiatric disorders, such as schizophrenia, Alzheimer disorders, and amyotrophic lateral sclerosis. Our results indicate that this endophenotype serves as a basis for the transdiagnostic characterization of these disorders.

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

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.