GABA signalling: therapeutic targets for epilepsy, Parkinson’s disease and Huntington’s disease

Abstract

Temporal lobe epilepsy (TLE), Parkinson's disease (PD) and Huntington's disease (HD) are neurodegenerative disorders that involve disruptions in gamma-amino butyric acid (GABA) signalling. GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). TLE seizures reflect excess excitation, which may result from local inhibitory circuit dysfunction. PD devastates the input to striatal GABAergic neurones and HD destroys striatal GABAergic neurones. Controlling GABA delivery to specific brain areas should benefit each of these diseases. The molecules responsible for GABA release and signalling are ideal targets for new therapies. In this paper, we discuss the role of GABA in the circuitry affected by each of these diseases and suggest potential sites for intervention. GABA is unique among neurotransmitters because it can be synthesised by either of two related enzymes. Intracellular GABA is found throughout the cytosol and in synaptic vesicles. GABA can be released either through exocytosis, or via the plasma membrane transporter. The synthesising enzyme probably determines the intracellular location and hence the mechanism for GABA release. Directing GABA synthesis, degradation, transport or receptors can control GABA signalling. We propose that new drugs and devices aimed at GABA synthesis, release and binding will offer novel and highly effective treatments for neurodegenerative diseases.

Evaluation of established human iPSC-derived neurons to model neurodegenerative diseases

“…Glutamatergic neurons, for example, more reflect Alzheimer's disease (AD) pathology (Vazin et al, 2014) while dopaminergic neurons are primarily affected in Parkinson's disease (PD) (Kriks et al, 2011). GABAergic neurons are mostly affected in Huntington's disease (Reiner et al, 1988) and play also an important role in AD, PD, epilepsy, multiple sclerosis and ALS (Pakaski et al, 1998;Kleppner and Tobin, 2001;Dutta et al, 2006;NietoGonzalez et al, 2011;Martin and Chang, 2012;Rossi et al, 2012). We have shown that iCell Ò neurons are mainly GABAergic and easy to transduce, creating the possibility to introduce disease related mutations by overexpressing or knocking out the gene of interest and look for a specific disease phenotype within short term cultures.…”

Inactivation of GABAA receptor is related to heat shock stress response in organism model Caenorhabditis elegans

“…Interestingly, GABA is the primary inhibitory neurotransmitter in vertebrate and invertebrate nervous systems. In fact, GABA neurotransmission abnormalities cause neurological diseases such as anxiety disorders and epilepsy in humans (Kleppner and Tobin 2001;Sieghart 1995).…”

Application of MS Transport Assays to the Four Human γ‐Aminobutyric Acid Transporters

“…[1] Ap ossible approach in the treatment of thesed iseases is to influence GABAergic neurotransmission. [1] Ap ossible approach in the treatment of thesed iseases is to influence GABAergic neurotransmission.…”

“…For determination of the pIC 50 values in this study,t he top and bottoml evels (i.e., Max and Min,r espectively)o fE quation(1) …”