How Staying Negative Is Good for the (Adult) Brain: Maintaining Chloride Homeostasis and the GABA-Shift in
Kelvin K Hui1,2, Thomas E Chater3, Yukiko Goda3,4
1Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States.
Frontiers in Molecular Neuroscience
|July 25, 2022
Summary
The GABA-shift, crucial for brain development and function, involves chloride ion transport and GABA neurotransmission. Dysregulation of this process is linked to neurodevelopmental disorders and may be a therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Excitatory-inhibitory (E-I) imbalance is implicated in neurodevelopmental disorders like autism, epilepsy, and schizophrenia.
- GABA neurotransmission's inhibitory function relies on chloride homeostasis, which changes during brain maturation (GABA-shift).
- Dysregulation of the GABA-shift and chloride transport is linked to circuit dysfunction in neurodevelopmental and neuropsychiatric disorders.
Purpose of the Study:
- To review the cell signaling and regulatory mechanisms of the GABA-shift.
- To highlight the roles of chloride cotransporters NKCC1 and KCC2 in the GABA-shift.
- To explore alterations in these processes in neurodevelopmental and neuropsychiatric disorders and potential therapeutic strategies.
Main Methods:
- Review of current scientific literature on GABA-shift, chloride homeostasis, and neurodevelopmental disorders.
- Analysis of the roles of NKCC1 and KCC2 chloride cotransporters.
- Discussion of interneuron interactions and their influence on the GABA-shift.
Main Results:
- The GABA-shift, a developmental process, is critical for establishing inhibitory GABA signaling.
- NKCC1 and KCC2 cotransporters are key regulators of neuronal chloride levels and the GABA-shift.
- Aberrant GABA-shift mechanisms, including altered cotransporter function, are observed in various neuropsychiatric conditions.
- Evidence suggests "dematuration" of neurons may contribute to E-I imbalance in adult disorders.
Conclusions:
- The GABA-shift is a dynamic process influenced by chloride cotransporters and neuronal interactions.
- Understanding GABA-shift dysregulation offers insights into neurodevelopmental and neuropsychiatric disorders.
- Targeting NKCC1 and KCC2 presents a promising therapeutic avenue for conditions associated with chloride homeostasis abnormalities.
Keywords:
GABA-shiftNa+-K+-2Cl– cotransporter-1 (NKCC1)chloride homeostasisneurodevelopmental disorders (NDD)neuropsychiatric disorders (NPD)potassium chloride cotransporter-2 (KCC2)More Related Videos
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