Major channels involved in neuropsychiatric disorders and therapeutic perspectives

Abstract

Voltage-gated ion channels are important mediators of physiological functions in the central nervous system. The cyclic activation of these channels influences neurotransmitter release, neuron excitability, gene transcription, and plasticity, providing distinct brain areas with unique physiological and pharmacological response. A growing body of data has implicated ion channels in the susceptibility or pathogenesis of psychiatric diseases. Indeed, population studies support the association of polymorphisms in calcium and potassium channels with the genetic risk for bipolar disorders (BPDs) or schizophrenia. Moreover, point mutations in calcium, sodium, and potassium channel genes have been identified in some childhood developmental disorders. Finally, antibodies against potassium channel complexes occur in a series of autoimmune psychiatric diseases. Here we report recent studies assessing the role of calcium, sodium, and potassium channels in BPD, schizophrenia, and autism spectrum disorders, and briefly summarize promising pharmacological strategies targeted on ion channels for the therapy of mental illness and related genetic tests.

Keywords: autism; bipolar disorders; ion channel openers; ion channels; ion channels blockers; schizophrenia.

FIGURE 1

(A) Kir4.1 channels localize on brain astrocytes both at perisynaptic and at perivascular processes and control spatial K⁺ buffering. (B) Upper panel: Pedigrees of two families harboring novel mutations in KCNJ10 associated to autism/epilepsy phenotype. Squares are males and circles females; solid black symbols represent affected children; slashes denote deceased individual. Lower panel: Schematic representation of the human Kir4.1 subunit with the two variants, R18Q and V84M. (B) Sample current families recorded from Xenopus oocytes expressing equal amounts of Kir4.1 WT (C), R18Q (D), or V84M (E) mRNA. Notice that mutant channels show increased current amplitudes compared to wild-type. Horizontal dashed lines indicate 0 current level. The pulse protocol is shown as inset in (C). From Sicca et al. (2011).