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Updated: Sep 23, 2025
Behavioral And Physiological Analysis In A Zebrafish Model Of Epilepsy
Published on: October 19, 2021
Perineuronal Nets Degradation and Parvalbumin Interneuron Loss in a Mouse Model of DEPDC5-Related Epilepsy
Tao Yang1, Shuntong Hu1, Wei-Chih Chang1
1Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Abstract:
DEPDC5, the key gene within the mechanistic target of rapamycin (mTOR) pathway, is one of the most common causative genes in patients with epilepsy and malformation of cortical development (MCD). Although somatic mutations in the dorsal cortical progenitors generate the malformed cortex, its pathogenesis of hyperexcitability is complex and remains unclear. We specifically deleted Depdc5 in the mouse forebrain dorsal progenitors to model DEPDC5-related epilepsy and investigated whether and how parvalbumin interneurons were non-cell autonomously affected in the malformed cortex. We showed that long before seizures, coincident with microglia inflammation, proteolytic enzymes degraded perineuronal nets (PNNs) in the malformed cortex, resulting in parvalbumin (PV+) interneuron loss and presynaptic inhibition impairment. Our studies, therefore, uncovered the hitherto unknown role of PNN in mTOR-related MCD, providing a new framework for mechanistic-based therapeutic development.
Insights
DEPDC5 mutations cause epilepsy and malformation of cortical development (MCD). This study reveals perineuronal net (PNN) degradation leads to parvalbumin interneuron loss and hyperexcitability in DEPDC5-related MCD.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- DEPDC5 mutations are a leading cause of epilepsy and malformation of cortical development (MCD).
- The exact mechanisms driving hyperexcitability in DEPDC5-related MCD remain unclear.
- Somatic mutations in dorsal cortical progenitors are known to cause cortical malformations.
Discussion:
- This study models DEPDC5-related epilepsy by deleting Depdc5 in mouse forebrain dorsal progenitors.
- It investigates the non-cell autonomous effects on parvalbumin interneurons within the malformed cortex.
- The research links microglia inflammation to proteolytic enzyme activity and perineuronal net (PNN) degradation.
Key Insights:
- Perineuronal net (PNN) degradation precedes seizures in DEPDC5-related MCD.
- PNN degradation results in the loss of parvalbumin (PV+) interneurons.
- Impaired presynaptic inhibition is a consequence of PV+ interneuron loss.
Outlook:
- This research uncovers a novel role for PNNs in mTOR-related MCD.
- It provides a new framework for developing mechanism-based therapies for DEPDC5-related neurological disorders.
- Targeting PNN degradation could offer a therapeutic strategy for epilepsy and MCD.
