Mesial Temporal Lobe Epilepsy (mTLE)
mTLE Project
Identify “Seizure-Causing” Cell Type in Surgically Resected Tissue from Epilepsy Patients
Mesial temporal lobe epilepsy (mTLE) is the most common focal epilepsy, associated with cognitive comorbidities, and refractory to medication in over 80 percent of patients.
Despite lacking a clear etiology, mTLE is generally associated with hippocampal sclerosis (HS), the most common ictogenic lesion encountered in patients with epilepsy.
While the CA3 and CA1 regions of the hippocampus in HS are damaged or even absent, the dentate gyrus (DG) is largely spared and believed to be a critical neural substrate for seizure generation and expression.
NeuN-DAB immunohistochemistry shows that the dentate gyrus resected from human mTLE patients have prominent granule cell layer dispersion compared with tissue resected from a tumor case.
It is well documented that DG in mTLE exhibits profound circuit reorganization that may disrupt the canonical wiring principles, or even change the complement of cell types specific to its local circuit.
Among these, the most prominent are the emergence of an atypical morphotype of dentate granule cells (DGCs with a basal dendrite in hilus (HBD), DGC-HBD, different from typical DGCs) and the extensive sprouting of DGC mossy fibers, which are believed to form aberrant recurrent excitatory connections among DGCs to promote seizures.
However, it still remains controversial as to whether these aberrant circuit components form functional connections, and if they do, what functional roles of these aberrant connections may play in seizure generations.
To directly address these questions, we take advantage of the wealth of live ictogenic human brain tissue resected from mTLE patients in the Texas Medical Center to prepare human brain slices for electrophysiology.
By leveraging a high-throughput multi-patching method (up to 12 cells) combined with morphology recovery, and high viability of human brain slices (alive >3 days), we are able to extensively examine how DGCs connect each other using these human mTLE samples, despite their low availability.
In addition, we are applying single-cell RNA-sequencing on surgical tissue samples to understand the relationship between aberrant neurogenesis on human DG, abnormal cell types and circuit disorganization.
We obtain our results directly from human patients and will help settle the controversies in the field. We will uncover a cohesive picture of how the DG circuit is reorganized to support the initiation and propagation of seizures, which may provide new strategies for mTLE treatments.