Biology subjects

Zavalin, K.

Publications and source records attributed to Zavalin, K..

3 recordsLinked to original sources

bioRxiv2026

4-Phenylbutyrate Rescue in GABRA1 Variants Associated with Developmental Epileptic Encephalopathies: from Cell and Mouse Models to Human

Disease variants in GABR genes encoding {gamma}-Aminobutyric acid type A receptor (GABAAR) subunits are major causes of developmental and epileptic encephalopathies (DEEs). There is no effective treatment for these DEEs although the GABAAR is a major target for antiseizure drugs. We previously identified the therapeutic effect of 4-phenyl-butyrate (PBA) in Gabrg2+/Q390X knockin DEE mice and now test the effect of the drug in GABRA1 variants that encode the 1 subunit. We used a multidisciplinary approach including in silico structural modeling, flow cytometry, patch clamp recordings and bio-chemistry in conjunction with differential tagging of the wild-type and the mutant alleles to evaluate the effect of PBA on rescue of GABAAR subunit expression, surface trafficking, and function in vitro in heterologous HEK293T cell model and in vivo in Gabra1+/A322D mice. We found that both total and cell surface 1 expression was reduced when the variant 1 protein was present; suggesting reduced functional receptor on the cell membrane and synapse. Patch clamp recordings identified 1 variants reduced GABA-evoked current amplitude. In silico prediction indicated reduced protein stability for GABRA1 variants indicated by negative {Delta}{Delta}G values. PBA increased both total and surface expression of wildtype 1 and 1 variants; and improved expression of both wildtype and variant 1 alleles when these were co-expressed. Importantly, PBA also increased the GABAAR expression in the thalamus of the Gabra1+/A322D mice. This study indicates that PBA is a promising treatment option for DEEs associated with GABRA1 mutations. Our previous work has demonstrated that PBA improves proteostasis by enhancing expression of the wildtype allele, repairing the mutant allele, and reducing endoplasmic reticulum stress. Therefore, it can mitigate seizures and improve neurobehavioral phenotypes at behavioral levels. Based on this and our previous work on GABRG2 and SLC6A1 mutations, we propose that PBA holds promise as a common medicine for multiple genetic neurologic disorders that share the proteostasis pathology with a broad clinical application in DEEs.

neuroscience↗

bioRxiv2026

Accumulation of Extracellular GABA, Impaired GABAergic Neurotransmission and 4-Phenylbutyrate Rescue in Mice of SLC6A1 Variant-Mediated Disorders

Mutations in SLC6A1 encoding GABA transporter 1 are a leading monogenic cause of developmental and epileptic encephalopathies, severe neurodevelopmental disorders lacking effective treatments. We previously demonstrated that 4-phenylbutyrate restored molecular and functional deficits, and reduced seizures in a Slc6a1 loss-of-function mouse, motivating a promising ongoing clinical trial. Here, we show this mouse exhibits accumulation of extracellular GABA, impaired neurotransmission, and reduced GABA uptake; and demonstrate that 4-phenylbutyrate rescues these abnormalities.

neuroscience↗

bioRxiv2021

Dendritic GABAergic inhibition controlled by Shh signaling-dependent stellate cell pool is critical for motor learning

Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and non-motor functions. The molecular layer interneurons (MLI), consisting of basket cells (BCs) and stellate cells (SCs), provide dendritic and somatic inhibitory synapses onto Purkinje cells, respectively. They are sequentially generated in an inside-out pattern from Pax2+ immature interneurons which migrate from the prospective white matter to the ML of the cortex. However, little is known as to how MLI subtype identities and pool sizes are determined, nor are their contributions to motor learning well understood. Here, we show that GABAergic progenitors fated to generate both BCs and SCs respond to the Shh signal. Conditional abrogation of Shh signaling inhibited proliferation of GABAergic progenitors and reduced the number of Pax2+ cells, whereas persistent Shh pathway activation increased their numbers. These changes, however, did not affect early-born BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are actively generated also resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of Shh signaling and their birth order and likely occurs after Pax2+ cells settle into their laminar positions in an inside-out sequence. Mutant mice with reduced SC numbers displayed decreased dendritic inhibitory synapses and neurotransmission onto Purkinje cells, resulting in an impaired acquisition of eyeblink conditioning. These findings also reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.

neuroscience↗