Stargazer Mouse Models
Stargazer Mouse Model Project
Generalized spike-wave (SW) absence seizures are the most common seizure disorder in children and are thought to be exclusively of genetic origin.
It remains unclear how each genetic lesion impairs cortical circuits, ultimately resulting in a seizure-prone abnormal neural
circuit.
The goal of this project is to unravel the complex cellular and molecular interplay as a result of gene mutation in seizure-prone neural circuits, thereby opening avenues for theavenues for the
The somatosensory cortex (S1) is a key brain region in the generation of absence seizures, with abnormal discharges originating in layers V-VI.
Revealing the stratification and cell-specific circuit changes in S1 is crucial for uncovering the mechanisms of absence seizures.
This project uses classic stargazer (stg, Cacng2/TARP), tottering (tg, Cacna1a/PQ Ca2+ channel alpha subunit) and Gabrg2 mutant mice (Gabrg2+/-, Gabrg2/ GABAAR γ2 subunit) for research.
● High-throughput multi-patch circuit mapping is used on specific fluorescent-labelled neurons.
This technique aims to investigate cell-type specific cortical circuit disruptions. The focus is on Layer V-VI of S1 in three different absence seizure mouse models.
●Employ single-cell RNA sequencing, including Patch-seq, to elucidate the specific expression of key pathogenic genes in certain S1 cell subgroups, in order to understand the disruptions in connections in a cell-type specific manner.
●Transgenic mice are utilized to manipulate layer-specific cell subgroups through chemogenetic and optogenetic techniques.
This approach is designed to either rescue or induce absence
seizures, thereby further confirming novel therapeutic targets for absence seizures.
● Compare the findings with the traditional thalamic-origin theory of absence seizures to further emphasize the significance of layer- and cell-type specific roles in cortical connections in the genesis of absence seizures.
Cortical-origin theory of absence seizures
Absence seizures originate in the somatosensory cortex.
From this focal region, the seizure activity propagates to other areas of the brain.
Among them, the cortical-thalamic loop plays a pivotal role in the spread and maintenance of seizure activity.
What kind of disruptions in the canonical wiring diagram of the S1 cortical region lead to the development of absence seizures?
Understanding the layer- and cell type-specific disruptions in connections among excitatory principal cells (PC), parvalbumin (PV), somatostatin (SOM), vasopressin (VIP), and neurogliaform cells (NGC) in S1 is crucial to unveiling the cortical circuit mechanisms of SW (spike-wave) absence seizures.
