The Alteration of Chloride Homeostasis/GABAergic Signaling in Brain Disorders: Could Oxidative Stress Play a Role?

Abstract

In neuronal precursors and immature neurons, the depolarizing (excitatory) effect of γ-Aminobutyric acid (GABA) signaling is associated with elevated [Cl−]i; as brain cells mature, a developmental switch occurs, leading to the decrease of [Cl−]i and to the hyperpolarizing (inhibitory) effect of GABAergic signaling. [Cl−]i is controlled by two chloride co-transporters: NKCC1, which causes Cl− to accumulate into the cells, and KCC2, which extrudes it. The ontogenetic upregulation of the latter determines the above-outlined switch; however, many other factors contribute to the correct [Cl−]i in mature neurons. The dysregulation of chloride homeostasis is involved in seizure generation and has been associated with schizophrenia, Down’s Syndrome, Autism Spectrum Disorder, and other neurodevelopmental disorders. Recently, much effort has been put into developing new drugs intended to inhibit NKCC1 activity, while no attention has been paid to the origin of [Cl−]i dysregulation. Our study examines the pathophysiology of Cl− homeostasis and focuses on the impact of oxidative stress (OS) and inflammation on the activity of Cl− co-transporters, highlighting the relevance of OS in numerous brain abnormalities and diseases. This hypothesis supports the importance of primary prevention during pregnancy. It also integrates the therapeutic framework addressed to restore normal GABAergic signaling by counteracting the alteration in chloride homeostasis in central nervous system (CNS) cells, aiming at limiting the use of drugs that potentially pose a health risk.

Dynamic and Systemic Perspective in Autism Spectrum Disorders: A Change of Gaze in Research Opens to A New Landscape of Needs and Solutions

“…A very rich literature supports the notion that oxidative stress occurs in ASD as well as in several, if not all, brain diseases and disorders [ 187 ]. Sources of oxidative stress are manifold and include inflammation, gut dysbiosis, xenobiotic and drug metabolism, maternal alcohol abuse, dysfunctional mitochondria.…”

“…Following the hypothesis that oxidative stress represents a hallmark of metabolic abnormalities in several brain disorders and given that it influences a wide array of molecular pathways, the possible impact of this imbalance was studied in relation to the impairment of chloride homeostasis occurring in the GABAergic system in CNS [ 187 ]. This study showed evidence linking the impairment of intracellular chloride concentration with the occurrence of oxidative stress and inflammation in patients with different neurological and neurodevelopmental diseases, such as ASD, epilepsy, schizophrenia, Down’s Syndrome [ 187 ]. Moreover, it showed that increased oxidative stress interferes with the shift of GABAergic transmission from excitation to inhibition, a fundamental ontogenetic process under epigenetic control [ 188 ].…”

“…The high frequency of drug resistance and the elevated risk of drug adverse side effects [ 218 ] suggest investigating the impact of systemic inflammation on the etiopathogenesis and progression of epilepsy in ASD [ 219 ]. Moreover, the link between epilepsy and oxidative stress [ 187 ] should not be overlooked, confirming the multiple and evolving effects of oxidative stress on the health of autistic people.…”

Is There a Glutathione Centered Redox Dysregulation Subtype of Schizophrenia?

“…Most of the recorded grey matter changes in schizophrenia occurs in the immediate post-onset phase [ 24 , 109 , 110 ], coinciding with the critical period of intracortical myelination [ 111 , 112 , 113 ]. Intracortical myelin mostly insulates parvalbumin containing interneurons [ 114 ] that are highly susceptible to developmental factors influencing redox balance [ 115 ] as well as GSH deficit and associated glutamate-mediated excitotoxicity [ 30 , 116 ]. In a subsample of patients reported by Pan and colleagues [ 73 ], we obtained quantitative intracortical myelin measurement and noted several regions where patients had lower intracortical myelin in the presence of higher glutamate, only when GSH levels were lower than the median (bilateral dorsolateral prefrontal cortex, right superior temporal, and left precentral gyrus and right subgenual ACC).…”

Physical Activity vs. Redox Balance in the Brain: Brain Health, Aging and Diseases

“…Hypomagnesemia, postulated in migraine, was shown to enhance glutamatergic neurotransmission, leading to increased oxidative stress [ 46 ]. It is worth mentioning that neurodevelopmental disorders, including Down’s syndrome, autism spectrum disorder, schizophrenia and epilepsy, were associated with oxidative stress-induced dysregulation of chloride ion homeostasis, which is related to γ-aminobutyric acid (GABA) signaling [ 47 ]. Interestingly, oxidative stress is also supposed to be involved in the course of bipolar disorder (BP).…”