Abstracts

Rationale: Stargazer mutant mice are a genetic model of autosomal recessive absence epilepsy with comorbid ataxia and abnormal head movements (Noebels et al., Epi Res 1990). The causative mutation has been mapped to Cacng2, a transmembrane AMPA receptor auxiliary subunit. CACNG2 variants have been implicated in bipolar disorder and lithium response, and a recent report links a CACNG2 splice site substitution to a case of self-limited focal epilepsy. In this study, we apply instrumented home-cage monitoring to systematically assess the mental status of Stargazer mutants (Stg/Stg).

Methods: Stg/Stg and wild type littermates at 7-8 weeks (n=22-24/group) were studied within Noldus Phenotyper homecages equipped with a shelter, two lickometered water-spouts (water Vs 0.8% sucrose), a feeding meter and a detachable running wheel. A modular design was employed as previously described (Jankovic et al., Plos One 2019, Bass et al., Front Neurosci 2020) to measure both unperturbed “baseline” behavior, as well as responses to a series of within-cage provocative maneuvers.

Results: On admission, Stg/Stg were significantly underweight (~23g vs 17g) and presented with early prominent hyperactive/hyper-exploratory behavior in response to cage novelty. Following this habituation period, and during the second of two subsequent 23h-long “baseline” recordings, Stg/Stg mice displayed lower sucrose preference and profound hypodipsia without hypophagia. While total or hourly distance measures were similar, mutants displayed greater rest and activity fragmentation, together with dampened peaks in ultradian periodicity. Stg/Stg mice exhibited a blunted response to an intense auditory (60s beep, 2300Hz) but not visual stimulus (60-minute light spot). Responses to a daytime shelter-removal or cage-swap perturbation were generally similar to WT mice. In contrast, when provided with a running wheel, Stg/Stg mice displayed a complete and total absence of wheel-running behavior.

Conclusions: By applying an objective, automated and experimenter-free assessment of spontaneous behavior, we report that Stargazer mutant mice display features of amotivation and disrupted rest and activity rhythms that may not be fully explained by spike/wave burden: ongoing experiments with wireless EEG seek to clarify this matter further. These results shed light on the pleiotropic effects of AMPA-receptor mis-trafficking and may provide additional behavioral endpoints for the development of novel antiseizure medications designed to address refractory epilepsy syndromes of generalized onset.

Funding: Please list any funding that was received in support of this abstract.: VK receives support from the NIH (1K08NS110924-01), an AES Junior Investigator Award (2020-2021), The Mike Hogg Fund, and seed funding from Baylor College of Medicine’s Office of Research.