The microglia-astrocyte axis pormotes disease progression in focal cortical dysplasia
Abstract number :
1.432
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2022
Submission ID :
2232848
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Yu Wang, MD, PhD – University of Michigan; Hsin-Yi Kao, PhD – University of Michigan; Yilong Yao – University of Michigan; Tao Yang, PhD – University of Michigan; Julie Ziobro, PhD – University of Michigan; Nurun Nahar Borna – University of Michigan; Daniel Leventhal – University of Michigan; Peng Li – University of Michigan,
This is a Late Breaking abstract
Rationale: The neuron- and mTOR-centric therapies are based on the conceptual paradigm that somatic mutations in a few cortical progenitors give rise to a malformed cortex and generate a severe seizure phenotype. However, FCDII patients don’t respond to anti-seizure medications (ASM) that primarily modulate neuronal channels or synaptic activities. On the other hand, mTOR inhibitors, proposed as the “precision medication,” are not superior to traditional ASM, suggesting a more complex molecular and cellular landscape underlying the malformed cortex.
Methods: We used CRISPR in-utero electroporation to knockout Depdc5 in rat forebrain dorsal progenitors and generated a clinically relevant FCDIIA rat model at genetic, molecular, cellular, clinical, and electrographic levels. We then used electrophysiology to determine the temporospatial frame of its epileptogenesis and disease progression. We applied spatial transcriptomics to profile the cellular and molecular dynamics and identified significant changes in the astrocyte-microglial axis that promotes cortical hyperexcitability.
Results: Depdc5 CRISPR-IUE rats showed the hallmark of mTOR hyperactivation, intrinsic epileptogenicity, and interictal and ictal fingerprints similar to those recorded in FCDII patients. Clinically, these FCDII animals showed striking progressive deterioration in seizure severity. Pathologically, dysplastic brains displayed progressive parvalbumin interneuron loss, microgliosis, and astrocytosis. Molecularly, there was a prominently elevated C3 expression restricted to the dysplastic cortex.
Conclusions: Our data suggested that the pathogenesis of FCD is complex, dynamic, and progressive, arising from a toxic and neurodegenerative microenvironment. Our data also provided novel mechanisms that could potentially shift the therapeutic paradigm for patients with FCDII or other mTORopathies.
Funding: U54NS117170, R01 NS113824
Basic Mechanisms