Enhanced GIRK2 channel signaling in Down syndrome: A feasible role in the development of abnormal nascent neural circuits

Abstract

The most distinctive feature of Down syndrome (DS) is moderate to severe cognitive impairment. Genetic, molecular, and neuronal mechanisms of this complex DS phenotype are currently under intensive investigation. It is becoming increasingly clear that the abnormalities arise from a combination of initial changes caused by triplication of genes on human chromosome 21 (HSA21) and later compensatory adaptations affecting multiple brain systems. Consequently, relatively mild initial cognitive deficits become pronounced with age. This pattern of changes suggests that one approach to improving cognitive function in DS is to target the earliest critical changes, the prevention of which can change the 'trajectory' of the brain development and reduce the destructive effects of the secondary alterations. Here, we review the experimental data on the role of KCNJ6 in DS-specific brain abnormalities, focusing on a putative role of this gene in the development of abnormal neural circuits in the hippocampus of genetic mouse models of DS. It is suggested that the prevention of these early abnormalities with pharmacological or genetic means can ameliorate cognitive impairment in DS.

Keywords: KCNJ6; depolarizing GABA; developmental GABA switch; early postnatal development; gabaergic neurotransmission; miR-155; neuronal excitability; synaptogenesis.

FIGURE 1

Major events during the formation of faulty neuronal circuits in the hippocampus of mouse genetic model of DS. (A). Main events in the hippocampus of normosomic mice. The time course of neurogenesis (black lines), synaptogenesis (green), GIRK2 expression (red), depolarizing-to-hyperpolarizing GABA switch (brown), and immature giant depolarizing potentials (GDP, purple). (B). Changes in GIRK2 expression levels (red), immature activity (violet), and neural circuit formation (green). Dashed lines show the changes in DS mice. Note the increase in GIRK2 levels and the prolongation of the period of immature activity in DS models. (C). Putative changes in the efficiency of GABAergic neurotransmission in the hippocampus of mouse genetic models during early postnatal development. Note a compensatory elevation of the depolarizing GABAergic efficiency before the GABA switch. The increased GABAergic excitation turns into an increased GABAergic inhibition after the GABA switch.