اختلال عملکرد سیستم GABA در اوتیسم و اختلالات مرتبط: از سیناپس تا علائم

Autism spectrum disorders (ASDs) are neurodevelopmental syndromes characterised by repetitive behaviours and restricted interests, impairments in social behaviour and relations, and in language and communication. These symptoms are also observed in a number of developmental disorders of known origin, including Fragile X Syndrome, Rett Syndrome, and Foetal Anticonvulsant Syndrome. While these conditions have diverse etiologies, and poorly understood pathologies, emerging evidence suggests that they may all be linked to dysfunction in particular aspects of GABAergic inhibitory signalling in the brain. We review evidence from genetics, molecular neurobiology and systems neuroscience relating to the role of GABA in these conditions. We conclude by discussing how these deficits may relate to the specific symptoms observed.

Autism spectrum disorders (ASDs) are a group of common neurodevelopmental syndromes. ASDs are diagnosed on the basis of qualitative behavioural abnormalities in three domains: social interaction, language and communication, and repetitive or restricted interests or behaviours (American Psychiatric Association, 2000). ASD symptoms are also observed in a number of neurodevelopmental disorders of known aetiology, including Fragile X Syndrome, Rett Syndrome, and Foetal Anticonvulsant Syndrome. While these disorders have very different underlying etiologies, their overlapping symptom profiles suggest that they may share a final common neurobiological pathway, which may also be present in idiopathic ASDs. However, the nature of this pathophysiology remains unclear. Emerging evidence suggests that this pathway critically involves impairments in particular aspects of inhibitory gamma-aminobutyric acid (GABA) neurotransmission. In this paper, we review the evidence of abnormalities in GABAergic neurons and synapses in neurodevelopmental disorders characterised by a shared symptomatology of ASD symptoms. A number of previous reviews have discussed selected aspects of this topic in detail, such as the evidence from molecular neurobiology and animal models (D’Hulst and Kooy, 2007, Pizzarelli and Cherubini, 2011, Rossignol, 2011 and Sgado et al., 2011). However, few authors have attempted to integrate this literature with the evidence from studies of human patients. The question of the mechanisms by which the hypothesised GABA deficits give rise to the characteristic symptoms of these disorders in humans, has likewise rarely been raised. In this paper, we begin by presenting a concise overview of the neurobiology of the human GABA system. See Fig. 1 for a graphical overview of the main components of this system. We then examine the evidence relating to the hypothesis that ASD and related disorders are characterised by particular abnormalities in this system. We conclude by discussing how these abnormalities might relate to the particular clinical features seen in these syndromes. Full-size image (34 K)

In this review, we have discussed the evidence that autism and related neurodevelopmental disorders are characterised by abnormalities in GABA function. Several converging lines of evidence – from genetics, epigenetics, animal models, and post-mortem studies of humans – point to a GABA deficit in autism, Fragile X Syndrome, and Rett Syndrome. Theoretical perspectives that may explain how these neurobiological abnormalities relate to the specific symptoms of these disorders were also discussed. However, despite the growing interest in the GABA hypothesis of autism and related disorders, there have been very few studies to directly examine the GABA system in the brain of living human patients. We believe that such studies are urgently warranted as, if these abnormalities are present and measurable in humans, this would have important implications both from a purely scientific perspective and also for future drug development. Other key challenges for the future include understanding how environmental, epigenetic and genetic factors interact to produce the complex features observed in neurodevelopmental disorders.