The role of glial-specific Kir4.1 in normal and pathological states of the CNS

Abstract

Kir4.1 is an inwardly rectifying K(+) channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K(+) homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent literature suggests Kir4.1 dysfunction facilitates neuronal hyperexcitability and may contribute to epilepsy. Genetic screens demonstrate that mutations of KCNJ10, the gene encoding Kir4.1, causes SeSAME/EAST syndrome, which is characterized by early onset seizures, compromised verbal and motor skills, profound cognitive deficits, and salt-wasting. KCNJ10 has also been linked to developmental disorders including autism. Cerebral trauma, ischemia, and inflammation are all associated with decreased astrocytic Kir4.1 current amplitude and astrocytic dysfunction. Additionally, neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis demonstrate loss of Kir4.1. This is particularly exciting in the context of Huntington disease, another neurodegenerative disorder in which restoration of Kir4.1 ameliorated motor deficits, decreased medium spiny neuron hyperexcitability, and extended survival in mouse models. Understanding the expression and regulation of Kir4.1 will be critical in determining if this channel can be exploited for therapeutic benefit.

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…The presence of several presynaptic markers at the plaque‐associated dystrophies (this work, Sanchez‐Varo et al, 2012, Trujillo‐Estrada et al, 2014) strongly suggests the presynaptic nature of these pathological structures. Similar findings have been also reported in another APP/PS1 model (Sadleir et al, 2016). However, we cannot rule out the possibility that some of these dystrophies are in fact axonal portions.…”

“…Therefore, transcellular degradation of neuronal dystrophies by astrocytes might directly support neuron survival or, alternatively, it might reduce the Aβ release from dystrophic presynaptic elements. In this sense, presynaptic dystrophies are sites of APP accumulation and putative Aβ release (Sanchez‐Varo et al, 2012; Torres et al, 2012) and, as recent studies indicate, the accumulation of BACE1 in presynaptic dystrophies surrounding plaques causes increased cleavage of APP and Aβ generation, which could lead to an exacerbation of amyloid pathology in AD (Sadleir et al, 2016; Torres et al, 2012). Alternatively, insulating dystrophies from the normal tissue might also decrease the probability of possible adverse inflammatory effects.…”

Chronic demyelination-induced seizures

“…In addition, both human postmortem tissue and animal models of seizure show reactive astrocytes, which exhibit increased expression of the intermediate filament glial fibrillary acidic protein (GFAP) and alteration of astrocyte channels, including the water channel aquaporin-4 (AQP4) and the inward rectifying potassium channel Kir4.1, both of which are central to epileptogenesis (Oberheim et al, 2008; Anderson and Rodriguez, 2011; Binder et al, 2012; de Lanerolle et al, 2012; Rodriguez-Cruces and Concha, 2015; Nwaobi et al, 2016). …”

Inhibition of Kir4.1 potassium channels by quinacrine

“…The reduced expression or dysfunction of Kir4.1 channels seems to be involved in several diseases (Loudon and Fry, 2014; Nwaobi et al, 2016). Recent studies showed that loss-of-function mutations of the human gene ( KCNJ10 ) encoding Kir4.1 channels are responsible for the SeSAME/EAST syndrome, an autosomal recessive disorder characterized by seizures, sensorineural deafness, ataxia, intellectual disability and electrolyte imbalance (Bockenhauer et al, 2009; Scholl et al, 2009; Reichold et al, 2010).…”