GABAergic inhibition shapes the connectivity, activity and plasticity of the brain. A series of exciting new discoveries provides compelling evidence that disruptions in a number of key facets of GABAergic inhibition have critical roles in the aetiology of neurodevelopmental disorders (NDDs). These facets include the generation, migration and survival of GABAergic neurons, the formation of GABAergic synapses and circuit connectivity, and the dynamic regulation of the efficacy of GABAergic signalling through neuronal chloride transporters. In this Review, we discuss recent work that elucidates the functions and dysfunctions of GABAergic signalling in health and disease, that uncovers the contribution of GABAergic neural circuit dysfunction to NDD aetiology and that leverages such mechanistic insights to advance precision medicine for the treatment of NDDs.
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This work was funded by a Bridge to Independence Award from the Simons Foundation Autism Research Initiative awarded to X.T., US National Institutes of Health (NIH) grant R01 MH104610 awarded to R.J., and NIH grant R01 MH085802 and a grant to the Simons Center for the Social Brain from the Simons Foundation Autism Research Initiative awarded to M.S. The authors also thank C. Clairmont for his substantial help with revising the manuscript, and X. Jing, M. Enriquez, K. Cruite, M. Gallagher, D. Tomasello, E. Wogram and E. Majercak for useful comments and discussions.
R.J. is a cofounder of Fate Therapeutics, Fulcrum Therapeutics and Omega Therapeutics.
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- NDD risk genes
Candidate genes identified from patient populations with clinically diagnosed neurodevelopmental disorders (NDDs) in which mutations are associated with increased risk of developing NDD symptoms.
- Transcription factors
Proteins that bind to specific DNA sequence motifs and regulate the transcriptional levels of target genes to determine cellular identity and function.
- Excitation–inhibition (E/I) imbalance
Disruption in the balance between excitatory and inhibitory drives that causes either overexcitation or underexcitation of neural circuits observed in various neurodevelopmental disorder subtypes.
- Stratification of patients
Rational partitioning of patients into subgroups, based on their behavioural metrics, biomarkers and genetic information, to facilitate precise diagnosis and targeted treatment.
- Precision medicine
An approach to medicine that considers the biological variabilities of each patient, such as sex, genetics and other biomarkers, for devising personalized treatment regimens.
- Epigenetic factors
Modifications to the chromosome, including methylation and histone modifications, that regulate the expression level of genes without altering the primary DNA sequence.
- GABA functional switch
A developmental process during which GABA action switches from excitatory to inhibitory, driven mainly by altered expression and function of the chloride transporters NKCC1 and KCC2.
- Homeostatic mechanism
Regulatory feedback signals involving changes in synapse number, synaptic strength and GABA signalling efficacy that stabilize neuronal and neural network excitability and function.
- Martinotti cells
Small multipolar interneurons, with short branching dendrites, that send projections to layer 1 and provide dendritic inhibition mainly for layer 5 pyramidal neurons to facilitate feedback inhibition.
- Critical period
A developmental stage often perturbed in neurodevelopmental disorders, and during which the connectivity of the nervous system is especially susceptible to long-term alterations by environmental stimuli.
- Ocular dominance plasticity
Changes in relative responses of visual cortex neurons to stimulation of the two eyes due to visual deprivation. This plasticity is triggered by changes in GABAergic inhibition.
- X-linked intellectual disability
A subset of male-biased intellectual disability cases that are associated with inheritance of mutant genes on the X chromosome.
- Somatic mosaic mutations
Genetic mutations that are absent in the zygote stage but present only in the progeny of mutant cells that occur during the developmental process.
- Chromatin looping
Dynamic process in which multiple distal genomic regions are brought into proximity through DNA–protein interactions to provide a structural basis for long-range gene transcription regulation.
- Syndromic forms of NDD
A clinical classification of neurodevelopmental disorder (NDD) characterized by patterned neurobehavioural phenotypes and defined genetic causes, including chromosomal aberrations, copy number variations and single gene mutations.
- Binocular rivalry
A visual phenomenon regulated by GABAergic inhibition in which different images presented to each eye compete for awareness, resulting in alternating perception.
- Transcription activator-like effector nucleases
(TALENs). Artificial DNases engineered through fusing a transcription activator-like effector DNA-binding domain to a DNA cleavage domain for the purpose of cutting and editing specific DNA sequences.
- Proteolysis-targeting chimeras
(PROTACs) Engineered small molecules composed of two distinct domain classes: one that engages E3 ubiquitin ligase and the other that binds to target proteins for degradation.
- Autism Diagnostic Observation Schedule
A standardized assessment tool that clinicians may use for diagnosing autism spectrum disorder in patients through the use of semistructured play or interview sessions.
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Tang, X., Jaenisch, R. & Sur, M. The role of GABAergic signalling in neurodevelopmental disorders. Nat Rev Neurosci 22, 290–307 (2021). https://doi.org/10.1038/s41583-021-00443-x