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Functional characterisation of the GABAA receptors
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
This differential inhibition proves to have some interesting properties. Recent studies carried out in hippocampal slice preparations demonstrated that the tonic inhibition was increased over 300% by the introduction of an inhibitor of GAT-1, the GABA transporter, but this failed to modulate phasic transmission. On the contrary, application of zolpidem increased phasic inhibition by 60% but failed to modulate tonic inhibition, due to the presence of a δ subunit in the extrasynaptic receptors (Nusser and Mody, 2002). It is thus clear that the subunit composition of receptor subtypes may provide a subtlety of response to agonist exposure, and thus neuronal inhibition, that is yet to be fully explored.
Antiepileptic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Tiagabine inhibits uptake of GABA into neurons by inhibiting GABA transporter, GAT-1. This leads to enhancement of GABAergic inhibitory neurotransmission required for the control of seizures (Sharma and Sharma, 2017).
Genetic and environmental determinants of adolescent alcohol use
Published in Ilana B. Crome, Richard Williams, Roger Bloor, Xenofon Sgouros, Substance Misuse and Young People, 2019
Toni-Kim Clarke, Richard C. Crist
Despite the relatively small impact of genetics on adolescent alcohol initiation and early use, there are some polymorphisms that have been associated with alcoholism in teenagers and young adults. A genome-wide association study (GWAS) in a British cohort found an association between alcohol use disorder symptoms in 18-year-olds and the single nucleotide polymorphism (SNP) rs193135937 (Edwards et al., 2015a). Although the polymorphism is intergenic and has no clear function, the association was significant at a genome-wide significance threshold (p ≤ 5 x 10−8) (Edwards et al., 2015a). A longitudinal GWAS study of 2,126 people found several loci significantly associated with the change in alcohol consumption levels through adolescence and into early adulthood (Adkins et al., 2015). These included variants in GABA transporter 1, SLC6A1 (solute carrier family 6 member 1) and mitofusin 1-like. GWASs of other psychiatric traits have suggested that a large number of polymorphisms with small odds ratios contribute to the risk for disease, but these are only identifiable with sample sizes in the tens of thousands. Thus, the GWAS of adolescent alcohol use only included ~2,130–4,300 individuals and was probably underpowered to find additional associations with relatively small effect sizes.
Effects of pyrethroids on the cerebellum and related mechanisms: a narrative review
Published in Critical Reviews in Toxicology, 2023
Fei Hao, Ye Bu, Shasha Huang, Wanqi Li, Huiwen Feng, Yuan Wang
It has been shown that motor coordination is modulated by extracellular GABA in the cerebellum. Activation of GABA-A receptor in the cerebellum impaired motor coordination (Hanchar et al. 2005). Also, the absence of GABA transporter subtype 1 in mice led to increased levels of extracellular GABA and impaired motor coordination as assessed by rotarod (Chiu et al. 2005). The increase of extracellular GABA levels in the cerebellum was also correlated with motor incoordination on the rotarod in rats (Boix et al. 2010). Moreover, the decrease of parvalbumin (PV) has been associated with a decline in innervation of GABAergic neurons, as reported by several studies (Cates et al. 1999; Schwaller et al. 2002; Iteire et al. 2020). In the Purkinje cell layer of the cerebellum, a group of PYRs showed reduced immunoreactivity to antibodies targeting PV. Thus, it is reasonable to suspect that changes in GABA levels may affect cerebellar neurons and cerebellar motor function.
Synaptic remodeling, lessons from C. elegans
Published in Journal of Neurogenetics, 2020
Andrea Cuentas-Condori, David M. Miller, 3rd
In C. elegans, as in mammals, GABA-dependent inhibition determines circuit function (Lehmann, Steinecke, & Bolz, 2012; Pelkey et al., 2017; Schuske, Beg, & Jorgensen, 2004). Strong conservation of key molecular determinants of GABAergic function, including the GABA biosynthetic enzyme, GAD (UNC-25), vesicular GABA transporter, VGAT (UNC-47) and GABA ionotropic (UNC-49) and metabotropic (GBB-1/2) receptors highlight striking molecular similarities and suggest that developmental mechanisms that control GABA-dependent circuit refinement might also be conserved (Jin et al., 1999; Mclntire et al., 1993a; 1993b). GABAergic neurons constitute about 20–30% of the mammalian cortex, typically provide inhibitory input to glutamatergic neurons and are structurally and functionally diverse (Hendry, Schwark, & Jones, 1987; Pelkey et al., 2017; Sherwood et al., 2010). Similar to DD neurons, some mammalian GABAergic neurons receive excitatory input through dendritic spines and others innervate target cells through en-passant boutons (Kawaguchi, Karube, & Kubota, 2006; Pelkey et al., 2017). GABAergic interneurons can also be extensively refined during postnatal development. Of particular interest, the elimination of perisomatic inputs from GABAergic basket cells to glutamatergic pyramidal neurons depends on a mechanism that requires GABA signaling (Sullivan et al., 2018; Wu et al., 2012). The parallel role of GABA in promoting the removal of presynaptic termini in developing DD neurons in C. elegans could be indicative of shared cell biological pathways for synaptic remodeling (Miller-Fleming, 2016).
Inter-organ regulation by the brain in Drosophila development and physiology
Published in Journal of Neurogenetics, 2023
Sunggyu Yoon, Mingyu Shin, Jiwon Shim
While the Or42a-Orco complex sets the basal level of GABA in the hemolymph via Kurs6+ neurosecretory cells to activate the GABAB receptor and maintain blood progenitor cells (Shim et al., 2013), Or49a stimulated by wasp odors generates an additional GABA flux and elevates the level of circulating GABA (Madhwal et al., 2020). Above a certain threshold, GABA is transported into blood progenitor cells via the GABA transporter (GAT) and converted into succinate through the GABA shunt pathway. Intracellular succinate inhibits Hph (Hypoxia inducible factor (HIF) prolyl hydroxylase) (Koivunen et al., 2007; Selak et al., 2005; Tannahill et al., 2013), leading to the stabilization of Drosophila Hif-1α, which primes blood progenitor cells to differentiate into lamellocytes. When parasitic wasps (Leptopilina boulardii) approach, larvae detect iridomyrmecin, a specific odorant generated by L. bourlardii via Or49a, and secrete a significantly higher amount of GABA into the hemolymph to elevate the immune potential. Therefore, larvae pre-conditioned with dead wasps exhibited increased circulating GABA levels, resulting in higher lamellocyte differentiation compared to wild-type controls. Moreover, the removal or inhibition of Or49a+ olfactory neurons led to an immuno-compromised phenotype. Together, these studies suggest that GABA plays dual roles as a signaling molecule via the GABAB receptor and as a metabolite in immune cell priming through the GABA transporter and GABA shunt pathways, highlighting the significance of the brain–blood interaction in hematopoiesis and immunity (Madhwal et al., 2020).