Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes

Abstract

Summary Mutations in the X-linked MECP2, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia, and encephalopathy with early lethality. RTT is characterized by apparently normal early development followed by regression, motor abnormalities, seizures, and features of autism, especially stereotyped behaviors. The mechanisms mediating these striking features are poorly understood. Here we show that mice lacking Mecp2 from γ-amino-butyric-acid-(GABA)-ergic neurons recapitulate numerous RTT and autistic features, including repetitive behaviors. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of RTT. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size consistent with presynaptic reduction in glutamic acid decarboxylase-1 and -2 levels and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal GABAergic neuronal function and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

Enhanced synapse remodelling as a common phenotype in mouse models of autism

“…NLG R451C mice show an increase in spontaneous inhibitory synaptic events 15 . Conditional KO of Mecp2 in inhibitory neurons induced a reduction in inhibitory signalling and autism-like stereotypies 9 . Mice with mutant Scn1a gene, which is responsible for Dravet's syndrome, show autistic-like behaviour and impairment in GABAergic transmission 11 .…”

“…Furthermore, mouse molecular genetics confirmed an impairment of synaptic functions, including GABA signalling and long-term potentiation/depression, in multiple ASD mouse models [8][9][10][11][12][13][14][15] . Although these studies provide strong evidence that supports a causal relationship between ASD-related gene mutations and synapse pathology, little is known about synapse formation and remodelling in the developing neocortex of these mouse models.…”

“…Rett syndrome, fragile X syndrome and tuberous sclerosis complex exhibit comorbidity with ASDs, and their corresponding mouse models were established and extensively studied [16][17][18][19] . Rescue experiments using these syndromic ASD mouse models successfully identified key molecular pathways involved in the pathology of neural circuits and behavioural deficits [9][10][11][20][21][22] . However, most ASD cases are non-syndromic, and recent genetic studies of non-syndromic ASDs identified a large number of candidates with rare genetic variants 6,7 .…”

Rett Syndrome: Reaching for Clinical Trials

“…A delay of the developmental switch in the expression of GluN2 subunits of the NMDA receptors in the visual cortex contributes to visual acuity deficits in Mecp2-deficient mice, which were improved by genetic deletion of the GluN2A subunit [109]; a negative allosteric modulator selective for GluN2A-containing NMDA receptors is currently in preclinical trials in Mecp2-deficient mice. Selective deletion of Mecp2 in GABAergic neurons caused impaired GABAergic transmission, cortical hyperexcitability, and several neurologic features of RTT and autism spectrum disorders [110]. Vigabatrin is an antiepileptic drug that irreversibly inhibits GABA transaminase, inhibits GABA catabolism, and thereby increases GABA levels [111].…”

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

“…In addition, using western blot, we measured regional brain levels of Glutamic acid decarboxylase (GAD), the rate-limiting enzyme in the conversion of excitatory neurotransmitter glutamate to inhibitory GABA in the brain [34]. This is because brain excitatory/inhibitory imbalance is increasingly linked to ASD [35][36][37][38], and both GAD65 and GAD67 isoforms, have been reported to be altered in ASD [39], and also in preclinical models of ASD such as the BTBR mouse [40] and the MIA model [41]. However, it is unknown whether prenatal VPA exposure alters GAD level postnatally.…”