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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Altered release and uptake of gamma-aminobutyric acid in the cerebellum of dystrophin-deficient mice

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Pereira da Silva, Janyerson Dannys [1] ; Campos, Diego Vannucci [1] ; Nogueira-Bechara, Fabiana Moreira [1] ; Stilhano, Roberta Sessa [2] ; Han, Sang Won [2] ; Sinigaglia-Coimbr, Rita [3] ; Lima-Landman, Maria Teresa R. [1] ; Lapa, Antonio Jose [4, 1] ; Souccar, Caden [1]
Total Authors: 9
[1] Univ Fed Sao Paulo, Escola Paulista Med, Dept Pharmacol, Sao Paulo, SP - Brazil
[2] Univ Fed Sao Paulo, Escola Paulista Med, Dept Biophys, Sao Paulo, SP - Brazil
[3] Univ Fed Sao Paulo, Electron Microscopy Ctr, Escola Paulista Med, Sao Paulo, SP - Brazil
[4] Univ Estado Amazonas, Manaus, Amazonas - Brazil
Total Affiliations: 4
Document type: Journal article
Source: NEUROCHEMISTRY INTERNATIONAL; v. 118, p. 105-114, SEP 2018.
Web of Science Citations: 2

Dystrophin deficiency caused by mutations of the related gene leads to muscle wasting in Duchenne muscular dystrophy (DMD). Some patients with DMD also present with intellectual disability and various degrees of neurological disorders, which have been related to a decreased number of postsynaptic gamma-aminobutyric acid type A receptors (GABA(A)Rs) in the hippocampus (HPC) and cerebellum (CBL). The aim of this study was to examine the relevance of dystrophin in the presynaptic GABAergic function in brain regions in which this protein is normally abundant. {[}H-3]-GABA release, induced by nicotinic receptor (nAChR) activation or K+ depolarization, and {[}H-3]-GABA uptake were determined using synaptosomes extracted from the cortex (CTX), HPC, and CBL of littermate control and mdx mice. Superfusion of the synaptosomes with nicotine or high K+ solutions led to a concentration-dependent and Ca2+-dependent {[}H-3]-GABA release in control and mdx synaptosomes. {[}H-3]-GABA release induced by 10 mu M nicotine in mdx CBL synaptosomes was 47% less than that in control mice. K+-induced {[}H-3]-GABA release did not differ between control and mdx synaptosomes. alpha 7-containing and beta 2-containing nAChRs were involved in nicotine-induced {[}H-3]-GABA release in control and mdx synaptosomes. Kinetic analysis of {[}H-3]-GABA uptake in mdx CBL synaptosomes showed a reduced (50%) half-maximal uptake time (t(1/) (2)) and increased (44%) rate of {[}H-3]-GABA uptake (V-max) compared to controls. The apparent transporter affinity (K-m) for GABA was not altered. Our findings show that dystrophin deficiency in mdx mice is associated with significant changes in the release and uptake of GABA in the CBL. These presynaptic alterations may be related to the reported decrease in postsynaptic GABA(A)R in the same brain region. The results indicate possible dysfunction of GABAergic synapses associated with dystrophin deficiency in the CBL, which may contribute to the cognitive and neurobehavioral disorders in mdx mice and patients with DMD. (AU)

FAPESP's process: 10/51344-3 - Presynaptic mechanisms involved in the cholinergic and GABAergic transmitter release in the central nervous system of the mdx mouse: analysis of nicotinic modulation in young and adult mice
Grantee:Caden Souccar
Support type: Regular Research Grants