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Global increases in seizure susceptibility in mice lacking 5-HT2C receptors: a behavioral analysis
1Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA. capplegate@mail.neurology.edu
Abstract:
Previous studies have shown that mice bearing a targeted disruption of the 5-HT2C receptor gene exhibit an epilepsy syndrome associated with sporadic spontaneous seizures that occasionally result in death. In this study, we have defined the seizure susceptibility profiles of these 5-HT2C receptor mutant mice backcrossed onto a C57BL/6 background. Wild-type and mutant animals were either electrically kindled from the olfactory bulb, exposed to corneal electroshock, or tested with the chemoconvulsant, flurothyl. In all paradigms, mice lacking the 5-HT2C receptor were significantly more seizure susceptible than wild-type controls. Results indicate that mutants have lower focal seizure thresholds, increased focal seizure excitability, and facilitated propagation within the forebrain seizure system. Mutants also exhibit lower generalized seizure thresholds for the expression of both generalized clonic and generalized tonic seizures. Importantly, the 5-HT receptor antagonist, mesulergine (2 or 4 mg/kg), administered prior to electroshock testing, recapitulated the mutant phenotype in wild-type mice. Together, these data strongly implicate a role for serotonin and 5-HT2C receptors in the modulation of neuronal network excitability and seizure propagation globally, throughout the CNS.
Insights
Mice lacking the serotonin 5-HT2C receptor show increased seizure susceptibility. Blocking this receptor in normal mice mimics this epilepsy phenotype, highlighting its role in controlling seizures.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Previous research indicates that mice with a disrupted 5-HT2C receptor gene develop epilepsy with spontaneous seizures.
- The 5-HT2C receptor plays a role in neurological function, but its specific impact on seizure susceptibility requires further definition.
Purpose of the Study:
- To characterize the seizure susceptibility profiles of 5-HT2C receptor mutant mice.
- To investigate the role of the 5-HT2C receptor in modulating neuronal excitability and seizure propagation.
Main Methods:
- 5-HT2C receptor mutant mice and wild-type controls were subjected to various seizure induction methods: electrical kindling, corneal electroshock, and chemoconvulsant (flurothyl) administration.
- The effects of the 5-HT2C receptor antagonist, mesulergine, were evaluated in wild-type mice.
Main Results:
- Mice lacking the 5-HT2C receptor exhibited significantly higher seizure susceptibility across all tested paradigms compared to wild-type controls.
- Mutant mice displayed lower focal seizure thresholds, increased focal seizure excitability, and enhanced seizure propagation.
- Lower generalized seizure thresholds for both clonic and tonic seizures were observed in mutant mice.
- Administration of mesulergine to wild-type mice replicated the heightened seizure susceptibility seen in the mutant mice.
Conclusions:
- The 5-HT2C receptor is crucial for modulating neuronal network excitability and controlling seizure propagation throughout the central nervous system.
- Serotonin signaling via 5-HT2C receptors represents a potential therapeutic target for epilepsy management.
