PubMed · 14482614
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
I B OSTRETSOVA, Ia SYTINSKII. 1962. [Glutamic acid decarboxylase].. https://pubmed.ncbi.nlm.nih.gov/14482614/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Epilepsy arises from disruption of excitation-inhibition (E/I) balance, typically due to excessive excitatory activity. Despite available therapies, a substantial proportion of patients remain treatment resistant. Enhancing inhibitory neuron activity via gene therapy can restore E/I balance and may therefore provide a therapeutic strategy for treatment-resistant epilepsy. Here, we developed a compact 410-bp glutamic acid decarboxylase 67 promoter (cmGAD67) that enables strong, selective transgene expression in inhibitory neurons while preserving adeno-associated virus (AAV) packaging capacity. Systemic delivery of AAV vectors carrying cmGAD67 preferentially targeted parvalbumin interneurons and enabled efficient circuit modulation. To evaluate therapeutic potential, we expressed glutamic acid decarboxylase 65 (GAD65) under the control of cmGAD67 (AAV-GAD65). AAV-GAD65 suppressed abnormal delta oscillations, reduced seizure-like activity, normalized anxiety-like behavior, and improved survival in seizure models. Biochemical analyses confirmed increased GABA levels in the cortex and hippocampus, linking functional improvements to enhanced inhibitory neurotransmitter synthesis. Together, these findings establish the cmGAD67 promoter as a versatile platform for inhibitory neuron-targeted AAV gene delivery and identify AAV-GAD65 as a promising strategy for seizure control and disorders associated with E/I imbalance.
Several lines of evidence suggest that the binding affinity of glutamate decarboxylase (GAD) to the active form of pyridoxine is low in cases of pyridoxine-dependent seizures (PDS) and that a quantitative imbalance between excitatory (i.e. glutamate) and inhibitory (i.e. gamma-aminobutyric acid, GABA) neurotransmitters could cause refractory seizures. However, inconsistent findings with GAD insufficiency have been reported in PDS. We report a case of PDS that is not accompanied by an elevated cerebrospinal fluid (CSF) glutamate concentration. Intravenous pyridoxine phosphate terminated generalized seizures which were otherwise refractory to conventional anti-epileptic medicines. No seizure occurred once oral pyridoxine (13.5 mg/kg per day) was started in combination with phenobarbital sodium (PB, 3.7 mg/kg per day). The electroencephalogram (EEG) normalized approximately 8 months after pyridoxine was started. The patient is gradually acquiring developmental milestones during the 15 months follow-up period. The CSF glutamate and GABA concentrations were determined on three separate occasions: (1) during status epilepticus; (2) during a seizure-free period with administration of pyridoxine and PB; and (3) 6 days after suspension of pyridoxine and PB and immediately before a convulsion. The CSF glutamate level was below the sensitivity of detection (<1.0 microM) on each of the three occasions; the CSF GABA level was within the normal range or moderately elevated. The CSF and serum concentrations of vitamin B6-related substances, before pyridoxine supplementation, were within the normal range. We suggest that (1) PDS is not a discrete disease of single etiology in that insufficient activation of GAD may not account for seizure susceptibility in all cases and (2) mechanism(s) of anti-convulsive effect of pyridoxine, at least in some cases, may be independent of GAD activation.
Explore the source record for details and available documents.