The role of GABAergic neural circuits in the pathogenesis of autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) comprises a heterogeneous range of neurodevelopmental conditions represented by symptoms including, communication and language deficits, repetitive, and restricted patterns of behavior and inadequate social interactions. Gamma‐aminobutyric acid (GABA) is known to mediate I responses in the central nervous system by interacting with GABA signaling receptors. In this context, several recent investigations suggest that imbalances in the GABAergic neurotransmission system may be implicated in the development of ASD as well as several other neurodevelopmental disorders, including Fragile X syndrome (FXS) and Rett syndrome. This review initially expounds the functional role of the GABAergic system in the mature brain and during neurodevelopment. This will be followed by discussions concerning the impact of deficiencies in the system on ASD and the other above‐mentioned neurodevelopment disorders. Finally, the connections between these deficiencies and behavioral features observed in the clinic will be considered.

Autism Spectrum Disorder: Focus on Glutamatergic Neurotransmission

“…As the developmental depolarizing-to-hyperpolarizing switch in GABA transmission is critical for the correct establishment of the E/I balance [ 274 ], alterations in GABAergic signaling can impair normal cellular processing and cause deficits such as those observed in ASD [ 275 ]. To date, increasing evidence of dysfunction in the GABAergic neurotransmission system has been reported in patients and animal models of ASD [ 276 , 277 ]. In vivo 1H-MRS measurements have revealed a significant increase in plasma levels of GABA in children with ASD compared to controls [ 81 , 85 , 278 ].…”

Cortical signatures of auditory object binding in children with autism spectrum disorder are anomalous in concordance with behavior and diagnosis

“…Quantifying the magnitude of the response within this time window showed that, overall, the growth in response magnitude with increasing coherence was significantly more sluggish in the ASD group than in the TD group (Fig 3C) Another component of the cortical response to temporal coherence is the induced gamma band (>30 Hz) activity, which has been associated with perceptual figure-ground segregation in vision [35]; with processing of complex sounds such as speech in audition [36,37], particularly with active listening [38]; and with temporal synthesis of information via predictive coding [39]. Gamma band activity is also thought to be mediated by inhibitory (GABAergic) mechanisms [40], which have been documented to be abnormal in ASD [41][42][43][44][45][46][47][48][49][50]. In the N = 18/20 coherent tones condition, the TD participants had increased gamma band power , especially during the later period (400 ms onwards) of the response (Fig 3D,top), while no such increase was observed in the ASD group (Fig 3D,bottom).…”

“…Computational models of gamma rhythms predict that these rhythms may be involved in coherence-dependent selective routing of sensory information to downstream regions [63]. Earlier in vitro studies using voltage-sensitive dyes, and more recent in vivo optogenetic studies, provide evidence that this coherence-dependent gating is mediated by GABAergic processing [40,64], which is known to be atypical in ASD [42][43][44][45][46][47][48][49][50]. However, unlike the evoked-response differences, these gamma band differences were observed later in time (400 ms and after) relative to the onset of coherent modulations.…”

Dendritic Integration Dysfunction in Neurodevelopmental Disorders

“…Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the adult mammalian brain. Dysfunction of inhibitory microcircuits within the neocortex has been linked to ASD and other NDDs through a variety of mechanisms including abnormal development, migration, intrinsic properties, or connectivity [275, 287, 288]. Different subtypes of GABAergic interneurons synapse onto discrete domains of excitatory neurons, including layer 5 pyramidal neurons in the mPFC, where they play unique roles in modulating pyramidal cell excitability and plasticity.…”