HT2CR Mutant Mice as a Model of Audiogenic Seizure Disorder

Audiogenic seizures were a prominent phenotype observed in constitutive 5-HT2CR -/Y mice following derivation of the initial breeding line. For example, brief exposure (2-18 s) to modulated tones of 5-19 kHz (at the low range of mouse hearing) at 108 dB could reliably evoke seizure activity in constitutive 5-HT2CR -/Y mice but not wild-type littermate mice (Brennan et al. 1997). These seizures were characterized as tonic-clonic in nature, and were often preceded by a period of repetitive snout grooming. Seizures occasionally recurred within a few minutes. Mice were also noted to have two to three seizure episodes per day (Tecott et al. 1995). Significantly, these seizures occasionally evolved to a tonic-extension phenotype, leading to respiratory arrest and mouse death. Seizure penetrance increased as a function of age. Exposure to seizure-evoking sound stimuli was relatively ineffective in 21- and 60-day-old constitutive 5-HT2CR -/Y mice; however, this same stimulus evoked seizures in 100% of mice tested at 120 and 180 days old (Brennan et al. 1997). Mutant mice were also noted to have significantly lower seizure thresholds in response to IV administration of the pro-convulsant drug pentamethylenetetrazol (metrazol).

Two aspects complicate interpretation of this seizure phenotype. First, the constitutive 5-HT2CR -/Y mice studied all retain some DBA/2 genetic loci. Mice of strain DBA/2 are known to have increased susceptibility to seizures. However, DBA/2 mice show this tendency early in their life, and seizure susceptibility loci identified within this strain are autosomally located. Furthermore, constitutive 5-HT2CR -/Y mice backcrossed five to eight times onto a pure C57BL/6 background continued to demonstrate phenotypic differences in susceptibility to olfactory bulb kindling, chemoconvulsant, or corneal electroshock evoked seizures (Applegate and Tecott 1998). These findings suggest that contributions from the DBA/2 strain were not significant factors influencing the seizure phenotype observed in constitutive 5-HT2CR mutant mice. Additionally, C57BL/6 J mice are known to have a well-described phenotype of middle-aged high frequency hearing loss. Microelectrode recordings of inferior colliculus cells in young animals demonstrated no phenotypic differences in neuronal auditory response. It is intriguing to note that the increase in constitutive 5-HT2CR -/Y mouse seizure susceptibility corresponds with the development of this high frequency hearing loss and remapping of auditory responses to the lower frequency sounds that are epileptogenic. The role of age-related high frequency hearing loss in C57BL/6 J mice was evaluated by breeding the 5-HT2CR mutation into B6.CAST-Cdh23Ahl+/Kjn mice, a strain con-genic to C57BL/6 J mice in all ways except for having a wild-type Ahl (age-related hearing loss) gene that prevents these mice from developing age-related hearing loss. In these mice, audiogenic seizure frequencies remained low in mutants without functional 5-HT2CRs, and no age-related increase in seizure incidence was appreciated (Tecott, personal communication).

Audiogenic seizures in constitutive 5-HT2CR -/Y mice evoked a widespread activation of CNS regions implicated in sound processing. c-fos expression indicative of cellular activity was noted in the external and internal cortex regions of the inferior colliculus, the dorsal lateral lemniscal nucleus, the medial geniculate nucleus of the thalamus, and the posterior intralaminar thalamic nucleus (Brennan et al. 1997). Intracellular recordings from the inferior colliculus, however, did not demonstrate significant phenotypic differences in neuronal responses to either sound frequency or volume. Constitutive 5-HT2CR -/Y mice were noted to have slightly increased response latencies to stimulation, a finding that has been correlated with a decreased ability to respond to repetitive auditory stimuli (Langner et al. 1987). Overall, these findings suggest that 5-HT2CRs have their most powerful effects on animal seizure susceptibility in the context of auditory sensory deprivation. Further studies are warranted to determine if this phenotype reflects disuse hypersensitivity of the inferior colliculus.

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