Decreased GABA(B) Receptors in the Cingulate Cortex and Fusiform Gyrus in Autism

Department of Anatomy and Neurobiology, Laboratory of Autism Neuroscience Research, Boston University School of Medicine, Boston, MA 02118, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 09/2010; 114(5):1414-23. DOI: 10.1111/j.1471-4159.2010.06858.x
Source: PubMed


J. Neurochem. (2010) 114, 1414–1423.
Autism is a behaviorally defined neurodevelopmental disorder and among its symptoms are disturbances in face and emotional processing. Emerging evidence demonstrates abnormalities in the GABAergic (gamma-aminobutyric acid) system in autism, which likely contributes to these deficits. GABAB receptors play an important role in modulating synapses and maintaining the balance of excitation-inhibition in the brain. The density of GABAB receptors in subjects with autism and matched controls was quantified in the anterior and posterior cingulate cortex, important for socio-emotional and cognitive processing, and the fusiform gyrus, important for identification of faces and facial expressions. Significant reductions in GABAB receptor density were demonstrated in all three regions examined suggesting that alterations in this key inhibitory receptor subtype may contribute to the functional deficits in individuals with autism. Interestingly, the presence of seizure in a subset of autism cases did not have a significant effect on the density of GABAB receptors in any of the three regions.

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Available from: Gene J Blatt, Oct 06, 2015
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    • "In addition to the role of GABA B R-mediated signaling in normal brain development, there exists a strong likelihood that changes in GABA B R function may be related to neurological disorders. Several recent reports indicate alterations in GABA B R function, number, and total protein in disorders such as autism (Fatemi and Folsom, 2009; Oblak et al., 2010 "
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    ABSTRACT: The GABA transmitter system plays a vital role in modulating synaptic formation and activity during development. The GABAB receptor subtype in particular has been implicated in cell migration, promotion of neuronal differentiation, neurite outgrowth, and synapse formation but it's role in development is not well characterized. In order to investigate the effects of brief alterations in GABAB signaling in development, we administered to rats the GABAB agonist baclofen (2.0 mg/kg) or antagonist phaclofen (0.3 mg/kg) on postnatal days 7, 9, and 12, and evaluated sensorimotor gating in adulthood. We also examined tissue for changes in multiple proteins associated with GABAB receptor function and proteins associated with synapse formation. Our data indicate that early postnatal alterations to GABAB receptor-mediated signaling produced sex differences in sensorimotor gating in adulthood. Additionally, we found differences in GABAB receptor subunits and kalirin protein levels in the brain versus saline treated controls. Our data demonstrate that a subtle alteration in GABAB receptor function in early postnatal life induces changes that persist into adulthood.
    International Journal of Developmental Neuroscience 10/2014; 41. DOI:10.1016/j.ijdevneu.2014.10.001 · 2.58 Impact Factor
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    • "Rubenstein and Merzenich (2003) have posited that reductions in GABAergic inhibitory activity may explain some symptomatology of autism, including increased incidence of seizures and auditory-tactile hypersensitivity (see also Casanova et al., 2003, 2006a,b). Oblak et al. (2010) found decreased GABA receptors in the cingulate cortex and fusiform gyrus in autism. These results may explain some symptomatology of autism, including increased incidence of seizures and sensory (e.g., auditory, tactile) hypersensitivity (Casanova et al., 2003). "
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    ABSTRACT: Objectives: Reports in autism spectrum disorders (ASD) of a minicolumnopathy with consequent deficits of lateral inhibition help explain observed behavioral and executive dysfunctions. We propose that neuromodulation based on low frequency repetitive Transcranial Magnetic Stimulation (rTMS) will enhance lateral inhibition through activation of inhibitory double bouquet interneurons and will be accompanied by improvements in the prefrontal executive functions. In addition we proposed that rTMS will improve cortical excitation/inhibition ratio and result in changes manifested in event-related potential (ERP) recorded during cognitive tests. Materials and methods: Along with traditional clinical behavioral evaluations the current study used ERPs in a visual oddball task with illusory figures. We compared clinical, behavioral and electrocortical outcomes in two groups of children with autism (TMS, wait-list group). We predicted that 18 session long course in autistic patients will have better behavioral and ERP outcomes as compared to age- and IQ-matched WTL group. We used 18 sessions of 1 Hz rTMS applied over the dorso-lateral prefrontal cortex in 27 individuals with ASD diagnosis. The WTL group was comprised of 27 age-matched subjects with ASD tested twice. Both TMS and WTL groups were assessed at the baseline and after completion of 18 weekly sessions of rTMS (or wait period) using clinical behavioral questionnaires and during performance on visual oddball task with Kanizsa illusory figures. Results: Post-TMS evaluations showed decreased irritability and hyperactivity on the Aberrant Behavior Checklist (ABC), and decreased stereotypic behaviors on the Repetitive Behavior Scale (RBS-R). Following rTMS course we found decreased amplitude and prolonged latency in the frontal and fronto-central N100, N200 and P300 (P3a) ERPs to non-targets in active TMS treatment group. TMS resulted in increase of P2d (P2a to targets minus P2a to non-targets) amplitude. These ERP changes along with increased centro-parietal P100 and P300 (P3b) to targets are indicative of more efficient processing of information post-TMS treatment. Another important finding was decrease of the latency and increase of negativity of error-related negativity (ERN) during commission errors that may reflect improvement in error monitoring and correction function. Enhanced information processing was also manifested in lower error rate. In addition we calculated normative post-error treaction time (RT) slowing response in both groups and found that rTMS treatment was accompanied by post-error RT slowing and higher accuracy of responses, whereas the WTL group kept on showing typical for ASD post-error RT speeding and higher commission and omission error rates. Conclusion: RESULTS from our study indicate that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions (RT, accuracy) during executive function test, and also by improvements in clinical evaluations.
    Frontiers in Systems Neuroscience 08/2014; 8:134. DOI:10.3389/fnsys.2014.00134
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    • "Post-mortem analysis on brain tissues from ASD patients as well as genetic and in vivo studies have largely contributed to unveil the impact of GABAergic signaling in these disorders. Thus, as compared to controls, a significant reduction in the density of GABAA, GABAB receptors, and benzodiazepine binding sites was detected in the supra and infragranular layers of the anterior cingulate cortex (known to participate in a variety of processes including socio-emotional behavior and other associative functions via prefrontal cortex connectivity) in brain samples from autistic subjects (39, 40). A reduction of 3[H]muscimol labeled GABAA receptors and 3[H]flunitrazepam labeled benzodiazepines binding sites was found also in the hippocampus (41, 55). "
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    ABSTRACT: γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, early in postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside the cell via the cation-chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. The depolarizing action of GABA leads to intracellular calcium rise through voltage-dependent calcium channels and/or N-methyl-d-aspartate receptors. GABA-mediated calcium signals regulate a variety of developmental processes from cell proliferation migration, differentiation, synapse maturation, and neuronal wiring. Therefore, it is not surprising that some forms of neuro-developmental disorders such as autism spectrum disorders (ASDs) are associated with alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits. In this review, we will discuss how changes of GABAA-mediated neurotransmission affect several forms of ASDs including the Fragile X, the Angelman, and Rett syndromes. Then, we will describe various animal models of ASDs with GABAergic dysfunctions, highlighting their behavioral deficits and the possibility to rescue them by targeting selective components of the GABAergic synapse. In particular, we will discuss how in some cases, reverting the polarity of GABA responses from the depolarizing to the hyperpolarizing direction with the diuretic bumetanide, a selective blocker of NKCC1, may have beneficial effects on ASDs, thus opening new therapeutic perspectives for the treatment of these devastating disorders.
    Frontiers in Pediatrics 07/2014; 2:70. DOI:10.3389/fped.2014.00070
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