GABA system dysfunction in autism and related disorders: From synapse to symptoms

Coghlan, Suzanne; Horder, Jamie; Inkster, Becky; Méndez, María Andreina; Murphy, Declan; Nutt, David

doi:10.1016/j.neubiorev.2012.07.005

Cited by 384 publications

(294 citation statements)

References 183 publications

(194 reference statements)

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“…Due to the widespread consequences that altered E/I balance has for brain function and behaviour (Haider, Häusser, & Carandini, 2013), E/I imbalance has been suggested as a possible explanation for the behavioural, cognitive and perceptual differences observed in those with ASD. While most accounts suggest that excitation may be increased relative to inhibition in ASD (Coghlan et al, 2012;Hussman, 2001;Markram, Rinaldi, & Markram, 2007;Rubenstein & Merzenich, 2003), others suggest that inhibition may be increased in ASD relative to excitation (Bertone, Mottron, Jelenic, & Faubert, 2005;Gustafsson, 1997a).…”

Section: Introductionmentioning

confidence: 99%

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations

2016

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The balance of neural excitation and inhibition (E/I balance) is often hypothesised to be altered in autism spectrum disorder (ASD). One widely held view is that excitation levels are elevated relative to inhibition in ASD. Understanding whether, and how, E/I balance may be altered in ASD is important given the recent interest in trialling pharmacological interventions for ASD which target inhibitory neurotransmitter function.Here we provide a critical review of evidence for E/I balance in ASD. We conclude that data from a number of domains provides support for alteration in excitation and inhibitory neurotransmission in ASD, but when considered collectively, the available literature provide little evidence to support claims for either a net increase in excitation or a net increase in inhibition. Strengths and limitations of available techniques are considered, and directions for future research discussed.3

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Section: Introductionmentioning

confidence: 99%

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations

2016

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“…GAD65 in VPA-treated groups was significantly lower than the control group in all brain areas sampled: CB (F (2,36) =9.046, p < 0.05), HP (F (2,36) =26.873, p < 0.05), MB (F (2,36) =4.700, p < 0.05), OB (F (2,36) =4.186, p < 0.05), PFC (F (2,36) =31.179, p < 0.05), STR (F (2,36) =7.210, p < 0.05). The effect in the majority of regions was independent of Sex, with the exception of a significant Drug × Sex interaction in CB (F (2,36) =8.816, p < 0.05) -VPA exposed males had lowest levels of GAD65; and in OB (F (2,36) =3.613, p < 0.05) -VPA-exposed females had lowest levels of GAD65…”

Section: Gad65 and Gad67 Western Blot Analysismentioning

confidence: 90%

“…The effect in the majority of regions was independent of Sex, with the exception of a significant Drug × Sex interaction in CB (F (2,36) =8.816, p < 0.05) -VPA exposed males had lowest levels of GAD65; and in OB (F (2,36) =3.613, p < 0.05) -VPA-exposed females had lowest levels of GAD65…”

Section: Gad65 and Gad67 Western Blot Analysismentioning

confidence: 90%

“…GAD67 in VPA-treated groups was significantly lower than the control group in MB (F (2,36) =41.445, p < 0.05), OB (F (2,36) =13.492, p < 0.05) and PFC (F (2,36) =13.267, p < 0.05), and was higher in CB (F (2,36) =5.615, p < 0.05), HP (F (2,36) =34.435, p < 0.05) and STR (F (2,36) =7.210, p < 0.05). Again in most regions this was independent of Sex; exceptions were a significant Drug × Sex interaction in MB and STR, where GAD67 differences were most prominent in male VPA-treated mice (Figure 4).…”

Section: Gad65 and Gad67 Western Blot Analysismentioning

confidence: 91%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Wei

Lam

et al. 2016

Behavioural Brain Research

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Rationale Rodents exposed to valproic acid (VPA) in prenatal life exhibit post-natal characteristics analogous to autism spectrum disorder (ASD). Many previous studies used relatively high doses of VPA during early pregnancy, potentially confounding interpretation because the offspring are the "survivors" of a toxic insult. Low dose or late gestation exposure has not been widely studied. Objectives We examined the behavioral sequelae of late gestation exposure to low dose VPA in the mouse. We also examined postnatal levels of glutamic acid decarboxylase (GAD65 and GAD67) as markers for GABA neurons, because GABA pathology and subsequent excitatory/inhibitory imbalance is strongly implicated in ASD. Methods Pregnant C57BL/6N mice received a single subcutaneous injection of 100 or 200 mg/kg on gestation day 17. The control group received a saline injection on the same day. The offspring were tested in a battery of behavioral tests in adolescence and adulthood. Six brain regions were harvested and GAD65 and GAD67 were measured by western blotting. Results Compared to saline-exposed controls, adult mice exposed to prenatal VPA had impaired novel object exploration and fear conditioning anomalies. GAD67 was decreased in midbrain, olfactory bulb, prefrontal cortex and increased in cerebellum, hippocampus and striatum; GAD65 was decreased in all 6 regions. ConclusionsOur results suggest that a low dose of VPA in late pregnancy has persistent effects on brain development, and in particular the GABA system, which 3 may be relevant to ASD. Further attention to the impact of gestation time and dose of exposure in VPA-induced ASD models is encouraged.

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Increased Functional Connectivity Between Subcortical and Cortical Resting-State Networks in Autism Spectrum Disorder

et al. 2015

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Importance Individuals with autism spectrum disorder (ASD) exhibit severe difficulties in social interaction, motor coordination, behavioral flexibility, and atypical sensory processing, with considerable interindividual variability. This heterogeneous set of symptoms recently led to investigating the presence of abnormalities in the interaction across large-scale brain networks. To date, studies have focused either on constrained sets of brain regions or whole-brain analysis, rather than focusing on the interaction between brain networks. Objectives To compare the intrinsic functional connectivity between brain networks in a large sample of individuals with ASD and typically developing control subjects and to estimate to what extent group differences would predict autistic traits and reflect different developmental trajectories. Design, Setting, and Participants We studied 166 male individuals (mean age, 17.6 years; age range, 7-50 years) diagnosed as having DSM-IV-TR autism or Asperger syndrome and 193 typical developing male individuals (mean age, 16.9 years; age range, 6.5-39.4 years) using resting-state functional magnetic resonance imaging (MRI). Participants were matched for age, IQ, head motion, and eye status (open or closed) in the MRI scanner. We analyzed data from the Autism Brain Imaging Data Exchange (ABIDE), an aggregated MRI data set from 17 centers, made public in August 2012. Main Outcomes and Measures We estimated correlations between time courses of brain networks extracted using a data-driven method (independent component analysis). Subsequently, we associated estimates of interaction strength between networks with age and autistic traits indexed by the Social Responsiveness Scale. Results Relative to typically developing control participants, individuals with ASD showed increased functional connectivity between primary sensory networks and subcortical networks (thalamus and basal ganglia) (all t ≥ 3.13, P < .001 corrected). The strength of such connections was associated with the severity of autistic traits in the ASD group (all r ≥ 0.21, P < .0067 corrected). In addition, subcortico-cortical interaction decreased with age in the entire sample (all r ≤ −0.09, P < .012 corrected), although this association was significant only in typically developing participants (all r ≤ −0.13, P < .009 corrected). Conclusions and Relevance Our results showing ASD-related impairment in the interaction between primary sensory cortices and subcortical regions suggest that the sensory processes they subserve abnormally influence brain information processing in individuals with ASD. This might contribute to the occurrence of hyposensitivity or hypersensitivity and of difficulties in top-down regulation of behavior.

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GABA system dysfunction in autism and related disorders: From synapse to symptoms

Cited by 384 publications

References 183 publications

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations

Measuring neural excitation and inhibition in autism: Different approaches, different findings and different interpretations

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

Increased Functional Connectivity Between Subcortical and Cortical Resting-State Networks in Autism Spectrum Disorder

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