<p>HDAC4 gene silencing alleviates epilepsy by inhibition of GABA in a rat model</p>

Abstract

ObjectivesDespite the availability of effective antiepileptic drugs, epileptic patients still suffer from intractable seizures and adverse events. Better control of both seizures and fewer side effects is needed in order to enhance the patient’s quality of life. We performed the present study with an attempt to explore the effect that HDAC4 gene silencing would have on epilepsy simulated by model rats. Furthermore, the study made additional analysis on the relativity of the HDAC4 gene in regard to its relationship with the gamma-aminobutyric acid (GABA) signaling pathway.Materials and methodsTremor rats were prepared in order to establish the epilepsy model. The rats would go on to be treated with si-HDAC4 in order to identify roles of the HDAC4 in levels of GABAARα1, GABAARα4, GAD65, GAT-1, and GAT-3. Finally, both electroencephalogram behavior and cognitive function of the rats following the treatment of si-HDAC4 were observed.ResultsLevels of the GABAARα1 and GABAARα4 showed an evident increase, while GAD65, GAT-1, and GAT-3 displayed a decline in the epilepsy rats treated with the aforementioned si-HDAC4 when compared with the epilepsy rats. After injection of si-HDAC4, the epilepsy rats presented with a reduction in seizure degree, latency and duration of seizure, amount of scattered epileptic waves, and occurrence of epilepsy, with an improvement in their cognitive function.ConclusionThe study highlighted the role that HDAC4 gene silencing played in easing the cases of epilepsy found in the model rats. This was shown to have occurred through the upregulation of both GABAARα1 and GABAARα4 levels, as well as in the downregulation of GAD65, GAT-1, and GAT-3 levels. The evidence provided shows that the HDAC4 gene is likely to present as a new objective in further experimentation in the treatment of epilepsy.

De novo CLPTM1 variants with reduced GABAAR current response in patients with epilepsy

“…43 Zhang et al suggested that after injecting si-HDAC4 (silencing of HDAC4) into epileptic model rats, GABA A R subunits α1 and α4 were highly increased, and severity, latency, duration of seizures, epileptic waves, and epileptic incidence were all reduced, with corresponding improvements in cognitive function. 44 The aforementioned results suggest that increased levels of GABA A R subunits α1 and α4 are a valid indicator for the improvement of epilepsy. Other studies have confirmed that homozygous mice cannot survive after GABRG2 knockout, whereas heterozygous mice after GABRG2 knockout can survive with anxiety symptoms and even have epileptic seizures in a special genetic background.…”

“…For example, in models of temporal lobe epilepsy (TLE), the expression and function of GABA A R subunits were altered (predominantly by decreased expression of GABA A R subunits and loss of function of GABA) 43 . Zhang et al suggested that after injecting si‐HDAC4 (silencing of HDAC4 ) into epileptic model rats, GABA A R subunits α1 and α4 were highly increased, and severity, latency, duration of seizures, epileptic waves, and epileptic incidence were all reduced, with corresponding improvements in cognitive function 44 . The aforementioned results suggest that increased levels of GABA A R subunits α1 and α4 are a valid indicator for the improvement of epilepsy.…”

Downregulation of GABAARα1 Aggravates Comorbidity of Epilepsy and Migraine via the TLR4 Signaling Pathway

“…The inhibitory neurotransmitter GABA is widely distributed throughout the nervous system [ 33 ]. The decrease in neuronal GABA content causes an increase in neural network excitability, which, in turn, induces abnormal high-frequency discharge [ 34 ]. Among all the GABAAR subunits, the GABAARα1 is the most widely expressed in neurons of the brain with high expression levels [ 35 ].…”

Drug‐resistant epilepsy: Drug target hypothesis and beyond the receptors

“… 29 Similar results were found in experimental models of seizures. Several histone deacetylases from class 1 29 , 30 and class 2 31 , 32 are upregulated during the status epilepticus –induced epileptogenesis. However, the class 2 member HDAC4 down‐modulates the gene expression of GABA A α1 subunit, 31 which is benzodiazepine‐sensitive 33 and the glutamatergic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor subunit GluA2.…”

“…Several histone deacetylases from class 1 29 , 30 and class 2 31 , 32 are upregulated during the status epilepticus –induced epileptogenesis. However, the class 2 member HDAC4 down‐modulates the gene expression of GABA A α1 subunit, 31 which is benzodiazepine‐sensitive 33 and the glutamatergic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor subunit GluA2. 34 The GluA2 subunit regulates calcium permeability of AMPA receptors, 35 and expression changes of this subunit is associated with many neurodevelopmental disorders, 36 tetramerizations, 37 and neuronal plasticity.…”