The Contribution of Dysfunctional Chloride Channels to Neurovascular Deficiency and Neurodegeneration.

Abstract

The brain is a metabolically demanding organ and its health directly depends on maintaining tissue oxygen that is sufficiently high to prevent hypoxia. Focal increases in oxygen demand, in response to sensory signals, motor output, etc., are supported by transient increases in cerebral blood flow via the hemodynamic response (Aksenov et al., 2016). Traditionally, specific products of glutamatergic and astrocytic pathways (i.e., nitric oxide (NO), arachidonic acid metabolites, calcium (Ca2+) and potassium (K+) ions) have been proposed as mechanistic contributors to the hemodynamic response (Archer et al., 1994; Attwell et al., 2010; Ross, 2012; Nippert et al., 2018). However, these mechanisms may not be sufficient drivers of the hemodynamic response. For example, a recent review (Nippert et al., 2018) concluded that, although NO must be present for vasodilation to occur in the cerebral cortex, it is not the active signaling molecule, arteriole vasodilation can occur in the absence of astrocyte Ca2+ increases, Ca2+ signals are characterized by long latencies occurring after the initiation of vasodilation and K+ siphoning through astrocytes does not always play a major role in neurovascular coupling. Moreover, hemodynamic modulatory pathways can have differing levels of influence across various structures. For instance, studies have shown that NO can be an active signaling molecule in the cerebellum (Akgoren et al., 1996; Yang and Iadecola 1997) and hippocampus (Lourenco et al., 2014). A possible addition to this conventional approach are chloride channel-dependent mechanisms of neurovascular coupling, which may participate in neurovascular deficiency and neurodegeneration. Prominent pathways which employ such chloride channels are gamma aminobutyric acid (GABA) ergic interneuron pathways, which operate via GABA-gated chloride channels (GABAA receptors) and provide a means of rapid signaling. The role of GABAergic interneurons and GABAA receptors in inhibition of neuronal activity is well-known. Interneurons suppress excessive neuronal activity and spatially limit neuronal responses by instigating the hyperpolarization of the cell membrane which has the added benefit of decreasing local oxygen consumption. Additionally, GABA-gated chloride channels can directly participate in regulating cerebral blood flow. GABAA receptors can be found along arterioles (Vaucher et al., 2000) where interneurons make direct morphological connections (Cauli et al., 2004; Tremblay et al., 2016). These chloride channels on brain vessels are functionally active and are able to facilitate substantial vasodilation in response to stimulation, attributable to the hyperpolarization of arteriolar smooth muscles with their subsequent relaxation. Multiple studies have shown that GABAergic interneurons are essential for the full expression of the hemodynamic response in the presence of chemical or electrical stimulation (Kocharyan et al., 2008), during epileptiform discharges (Saillet et al., 2016) as well as in response to both sensory (Aksenov et al., 2019) and optogenetic stimulation (Anenberg et al., 2015). Arteriolar GABA-gated chloride channels, can therefore play an important role in the hemodynamic response due to their fast and profound effect on vasodilation. In essence, GABA-gated chloride channels can function to prevent hypoxia by both upregulating oxygen supply and downregulating oxygen consumption. Thus, it is our perspective that if the number of these channels or their main biochemical properties are affected, the combination of decreased inhibition and a weakened hemodynamic response can induce local hypoxia, which will alter the intracellular and extracellular environment with neurodegeneration evident thereafter. In support of this perspective, we will briefly review chloride channel dysfunction and neurodegeneration in different diseases, and then provide our interpretation regarding the role of neurovascular deficiency as a medium between chloride channel dysfunction and neurodegeneration.