The Role of GABA-Shift in Neurodevelopment and Psychiatric Disorders

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Background

An intriguing feature of the GABAergic system is the fact, that cell membranes' responsiveness to stimulation is mediated by GABAA receptors that change their direction of electrical activity during development, a process described as the GABA-shift. The mechanisms behind the GABA-shift is a balanced change in the expression and functions of key transport proteins for Cl- and bicarbonate. In the immature brain, Cl- uptake by NKCC1 causes an increase in intracellular Cl- concentration ([Cl-]i) resulting in neurons' depolarization upon GABAA receptor activation. During neurodevelopment, NKCC1 expression in neurons is reduced, while the Cl- exporter KCC2 is more expressed, resulting in a shift of GABAA receptor-mediated responses towards hyperpolarization. The neurodevelopmental trajectory, but also the functional regulation of the Cl- transporters, define the physiological properties of the excitatory/inhibitory balancing underlying the GABA-shift.



The developmental GABA-shift has been examined from isolated in-vitro cell culture models to in-vivo conditions. A cell-type-specific temporal pattern of the GABA-shift has been identified in some neuronal subpopulations, and the requirement of depolarizing GABAergic responses for several neurodevelopmental processes has been demonstrated. Accordingly, any dysregulation of the developmental trajectory is associated with developmental neuropathological and psychiatric disorders. Finally, many neuropathological conditions are accompanied by a GABA-shift back to immature conditions.

It is therefore imperative to understand the molecular mechanisms and processes that regulate a normal and abnormal GABA-shift to better understand how such developmental neuropathological and psychiatric disorders manifest and can be perhaps treated.



With this Research Topic we aim to highlight the importance of this long investigated and fascinating theme, providing a forum to discuss:

(i) basic research on the mechanisms and regulation of the GABA-shift;

(ii) novel neuroscience methods that advanced research on this topic;

(iii) the implication of the GABA-shift in neuronal and neuropsychiatric disorders;

(iv) future goals and directions elucidating the developmental and clinical relevance of the GABA-shift.



An in-depth investigation will be carried out by exploring the neurophysiological establishment of the GABA-shift, as well as the neuropathological conditions that result in abnormal neurodevelopment, focusing on the following subtopics:



• Molecular pathways that determine the precise neurodevelopmental trajectory of the GABA-shift and it’s dysregulation after neurological insults;

• New molecular engineering technologies for advancing research in the field such as reliable markers to investigate the GABA-shift in real-time under in-vitro and in-vivo conditions;

• Brain excitation-inhibition (E/I) regulation and/or imbalances, in particular, related to epilepsy;

• Neurodevelopmental disorders related to GABA-shift anomalies such as Rett syndrome, Autism disorders, Fragile X syndrome, West syndrome, etc.;

• Neuropsychiatric disorders related to GABA-shift abnormalities;

• Neurotoxicant insults that alter the GABA-shift.



We welcome submissions of reviews and original research addressing this fundamental biological question from a broad range of perspectives and using morphological, electrophysiological, behavioral, systems neuroscience, and/or computational approaches.

We also welcome integrative approaches that show the occurrence and underlying mechanisms of the GABA-shift in other areas of the nervous system (e.g., spinal cord, PNS, enteric nervous system), in other organ systems (e.g., pancreas, testis, etc.), and in non-mammalian or invertebrate animals. Insights gained from these approaches will help to understand the evolutionary relevance of the intriguing observation, as well as the functional consequence of the GABAergic system in regulating both appropriate neurodevelopment and altered neuropathological conditions.

Keywords: GABA-Shift, GABAergic Neurodevelopment, Inhibitory Disorders, Excitation: Inhibition Balancing, Inhibitory Regulation, Excitation, Inhibition

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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