The role of GABAergic signalling in neurodevelopmental disorders

Abstract

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.

Fig. 1 |. Development of the GABAergic signalling system.

a | In the mammalian brain, GABAergic interneurons are generated in proliferative regions including the medial ganglionic eminence (MGE), lateral ganglionic eminence (LGE), caudal ganglionic eminence (CGE) and the preoptic area (POA), and then migrate around the lateral ventricle (LV) to the subcortical and cortical destination areas, where they undergo further specification^, . Recent advances in stem cell biology enable the generation of GABAergic neurons in vitro using directed differentiation from pluripotent stem cells (PSCs) to neural progenitor cells (NPCs), then to functional human GABAergic neurons. Also, somatic cells such as fibroblasts can be transdifferentiated into GABAergic neurons through ectopic expression of transcription factors. b | A simplified diagram that shows the connectivity of the main subtypes of interneurons, including parvalbumin-expressing (PV⁺), somatostatin-expressing (SST⁺), vasoactive intestinal peptide-expressing (VIP⁺) and reelin-expressing (RELN⁺) neurons. The number of interneurons also undergoes dynamic changes during development as the neurons integrate into brain networks.c | GABAergic signalling regulates neural network excitability through three main mechanisms: fast phasic inhibition mediated by synaptic GABA_A receptors (GABA_ARs); slow tonic inhibition mediated by extrasynaptic GABA_ARs; and the dynamic regulation of the intracellular chloride concentration by the chloride transporters NKCC1 and KCC2, which determines the polarity and efficacy of GABAergic inhibition. d | GABAergic inhibition has major roles in modulating neural network oscillations and brain circuit plasticity during development and in adults. The developmental plasticity window is closed in adult animals such that monocular deprivation no longer changes the eye-specific projection pattern to the visual cortex, indicated by the differently coloured stripes. Blocking GABAergic inhibition in adult animals reactivates visual cortex plasticity. CC, current clamp; LFP, local field potential.

Fig. 2 |. Pathogenic mechanisms underlying neurodevelopmental disorders.

A large fraction of NDDs are caused by genetic mutations and epigenetic aberrances occurring at the whole-organism or somatic levels that cause deficits in the expression level, localization and interaction pattern of the RNA and protein molecules. Such a plethora of perturbations engage a number of GABA-related disease mechanisms at the circuit level, which lead to physiological and cognitive impairments present in different subtypes of NDD.

Fig. 3 |. Therapeutic opportunities at the genetic level for managing NDDs.

Gene replacement therapies utilize virus to introduce a functional transgene copy to restore mRNA and protein production (A), whereas gene editing therapies employ technologies such as CRISPR/Cas9 to correct mutant genes at their endogenous loci (B). Catalytically-inactive Cas9 can be repurposed to modify the epigenetic status of specific genes to activate or silence their expression without changing the primary DNA sequence (C). RNA-based therapies modulate gene expression levels in the target cells by delivering mRNA, which can be further translated into protein products (D); or by delivering RNA interference (RNAi) and antisense oligonucleotides (ASO) to knock down particular RNA transcripts (E).

Fig. 4 |. Therapeutic opportunities at the molecular level for managing NDDs.

Various drugs have been developed to modulate the molecular processes in the cells through: binding with the target proteins to alter their biological activities (A), modulating the activities of molecular signalling pathways (B), altering the interactions between the target proteins and other proteins (C), facilitating the degradation of target proteins (D). Moreover, novel therapeutics have been developed to modulate the expression levels of the genes that encode the target proteins (E).

Fig. 5 |. Therapeutic opportunities at the circuit levels for managing NDDs.

At the circuit level, drugs have been developed to regulate the excitability of neurons through modulating the activity or expression of ion channels and receptors (A). Neuronal chloride transporters are master regulators of the polarity and efficacy of GABAergic signaling, therefore presents a good target for therapeutic development (B). Experimental therapeutic modalities are also under development to engage endogenous neuromodulatory mechanisms such as oxytocin (C), to directly modulate the activity of target neuronal population with optogenetics or chemogenetics (D), and to restore the density of inhibitory neurons through transplantation of in vitro differentiated GABAergic interneurons (E).

Fig. 6 |. Therapeutic and diagnostic opportunities at the individual level for NDDs.

Symptomatic diagnosis of disease-related phenotypes (A), combined with clinically relevant biomarkers such as EEG, fMRI, blood and CSF biomarkers (B), assist the diagnosis and stratification of patients to receive precision medicine treatment (C). Moreover, various brain stimulation methods including deep brain stimulation (DBS), transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS) (D) and behavior therapies (E) may also systematically ameliorate NDD symptoms.