Authors :
Presenting Author: Yuliya Voskobiynyk, PhD – Gladstone Institutes
Britta Lindquist, MD, PhD – Gladstone Isntitutes
Kimberly Goodspeed, MD – UT Southwestern
Vivianna DeNittis, BS – Gladstone Institutes
Deanna Necula, BS – Gladstone Institutes
Jeanne Paz, PhD – Gladstone Institutes
Rationale:
The solute carrier family 6 member 1 (SLC6A1) gene has been recently implicated in a spectrum of neurodevelopmental disorders, including epilepsy, autism, and intellectual and motor disability, collectively named SLC6A1 syndrome. Additionally, the largest exome sequencing study of autism patients to date identified SLC6A1 among the top 10 genes with the most significant variant enrichment. 91% of patients with SLC6A1 mutations develop intractable myoclonic atonic epilepsy, and 82% experience a developmental delay. SLC6A1 syndrome is likely to involve dysfunction of the thalamus, a subcortical structure known for its central role in seizures, sleep, attention, and cognitive processing — all physiological processes known to be disrupted in patients with mutations in the SLC6A1 gene. The SLC6A1 gene encodes the GABA transporter GAT-1, which regulates extracellular levels of GABA and consequently controls brain excitability. The cellular and circuit mechanisms by which SLC6A1 mutations cause SLC6A1 syndrome remain unknown, thus hampering the development of effective treatments.
Methods:
To fill this gap, we focused on dissecting the mechanisms that cause epilepsy in a new mouse model carrying a human SLC6A1 mutation. The recent generation of transgenic mouse models of SLC6A1 syndrome containing human mutations provides a previously unavailable tool to understand the mechanisms responsible for SLC6A1 syndrome. We used the first mouse model of SLC6A1 syndrome, in which the human S295L mutation, a toxic point mutation found in SLC6A1 patients, has been knocked into the mouse Slc6a1 gene. Results:
Here, we report electrographic (ECoG) recordings and clinical data from a patient with S295L variant in SLC6A1 who was diagnosed with motor deficits and childhood absence epilepsy. Next, we show that mice bearing the S295L mutation (GAT-1S295L/+) have motor deficits and absence-type seizures. The spike-and-wave discharges are similar in GAT-1S295L/+ and GAT-1+/– mice and follow the same pattern of pharmacosensitivity, being bidirectionally modulated by ethosuximide and the GAT-1 antagonist NO-711. Simultaneous EEG and thalamic unit recordings in freely behaving mice showed that spike-and-wave discharges are time-locked with high-frequency bursting in thalamocortical neurons. These findings are consistent with a loss-of-function deficit in GAT-1S295L/+ mice and absence epilepsy.
Conclusions:
In conclusion, ECoG findings in GAT1S295L/+ mice phenocopy GAT-1 haploinsufficiency and provide a useful preclinical model for drug screening and gene therapy investigations. In our ongoing studies, we are focused on determining 1) the impact of GAT-1 haploinsufficiency on thalamocortical neuron and circuit excitability and 2) the impact of GAT-1 haploinsufficiency-induced epileptic activity on sleep.
Funding: NOMIS-Gladstone Fellowship, NIH/NINDS
1F32NS127998-01, CIRM Scholar Award