Spatiotemporal expression patterns of genes coding for plasmalemmal chloride transporters and channels in neurological diseases

Abstract

Neuronal voltage changes which are dependent on chloride transporters and channels are involved in forming neural functions during early development and maintaining their stability until adulthood. The intracellular chloride concentration maintains a steady state, which is delicately regulated by various genes coding for chloride transporters and channels (GClTC) on the plasmalemma; however, the synergistic effect of these genes in central nervous system disorders remains unclear. In this study, we first defined 10 gene clusters with similar temporal expression patterns, and identified 41 GClTC related to brain developmental process. Then, we found 4 clusters containing 22 GClTC were enriched for the neuronal functions. The GClTC from different clusters presented distinct cell type preferences and anatomical heterogeneity. We also observed strong correlations between clustered genes and diseases, most of which were nervous system disorders. Finally, we found that one of the most well-known GClTC, SLC12A2, had a more profound effect on glial cell-related diseases than on neuron-related diseases, which was in accordance with our observation that SLC12A2 was mainly expressed in oligodendrocytes during brain development. Our findings provide a more comprehensive understanding of the temporal and spatial expression characteristics of GClTC, which can help us understand the complex roles of GClTC in the development of the healthy human brain and the etiology of brain disorders.

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“…NKCC1 is expressed in oligodendrocytes (Wang et al, 2003;Yu et al, 2018), microglia (Luo et al, 2021;Tóth et al, 2022), and astrocytes (Su et al, 2002). KCC2 expression is absent in glia cells (Huang et al, 2023). GABAergic receptor expression has been observed in all glia cells, including oligodendrocytes (Williamson et al, 1998;Arellano et al, 2016), microglia (Favuzzi et al, 2021;Logiacco et al, 2021), and astrocytes (Yoon et al, 2012;Mederos et al, 2021).…”

“…Examination of KCC2 expression in human brain regions (Figure 3B) shows that high levels are expressed in hippocampus, mesencephalon, and cingulate gyrus. KCC2 expression is known to be present in only neurons, rather than glia cells (Williams et al, 1999;Huang et al, 2023). KCC2 is present in regions that regulate cognitive functions consisting of cortical areas and hippocampus, and is also abundantly expressed in mesencephalon and brainstem.…”