Clinicopathologic Dissociation: Robust Age-dependent Lafora Body Accumulation in Malin-KO Mice Without Observable Changes in Home-cage Behavior
Abstract number :
1.106
Submission category :
2. Translational Research / 2D. Models
Year :
2023
Submission ID :
165
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Vaishnav Krishnan, MDPhD FAES – Baylor College of Medicine
Jun Wu, PhD – University of Texas Southwestern Medical Center; Arindam Ghosh Mazumder, PhD – Neurology – Baylor College of Medicine; Jessica Kamen, BS – Neurology – Baylor College of Medicine; John Bass III, BS, MS – Neurology – Baylor College of Medicine; Atul Maheshwari, MD FAES – Neurology – Baylor College of Medicine; Berge Minassian, MD – University of Texas Southwestern Medical Center
Rationale:
Lafora Disease is an autosomal recessive progressive myoclonic epilepsy associated with cumulative neurocognitive deterioration. In this study, we sought to identify reliable and robust preclinical endpoints of neurobehavioral deterioration in a Lafora genetic mouse model that may be applied to test a wealth of targeted genetic treatments in development.
Methods:
All protocols were approved by the BCM IACUC. At 6 weeks, ~6-7 months and ~12-14 months of age, malin deficient mice (EPM2b-/-) and their wild type (WT) littermates underwent a standardized home-cage behavioral assessment designed to appraise features of rest/arousal, consumptive behaviors, risk aversion and exercise motivation (n~18-27/group, ~50% female). At each timepoint, we quantified the burden of polyglucosan accumulation, gliosis and microglial activation using a combination of periodic acid Schiff-D staining and immunohistochemistry (glycogen synthase, GFAP and IBA-1, n~3-4/group). At the last time point, we additionally examined their behavioral responses to a 30mg/kg injection of PTZ (pentylenetetrazole). We applied wireless EEG (EMKA technologies) in a separate cohort of mice to screen for spontaneous seizures (7-10 mice/genotype, ~96h/mouse).
Results:
A clear age-dependent increase in Lafora body accumulation, gliosis and microglial activation was evident. However, across all three age groups, WT and littermate EPM2b-/- mice were essentially indistinguishable across a range of home-cage metrics of horizontal activity, shelter engagement, feeding/drinking rhythms, wheel-running and behaviorally defined sleep. Within WT mice, we observed clear age-related mild nocturnal hypoactivity, a diminished startle response and reduced wheel-running, but similar changes were seen in EPM2b-/- mice. At 12-14 months of age, we did not detect any spontaneous seizures in EPM2b-/- mice and spectral features of the waking EEG were similar across genotypes. PTZ elicited a greater frequency of clonic seizures in EPM2b-/- mice, which also displayed a slightly more pronounced post-ictal suppression of movement, feeding and drinking behavior over the subsequent day.
Conclusions:
While EPM2b-/- mice faithfully recapitulate the neuropathological hallmarks of Lafora disease, we find no evidence for an associated progressive neurobehavioral deterioration, as ascertained through an objective, continuous and experimenter-free form of behavioral telemetry and continuous EEG. This clinicopathologic dissociation may reflect distinct species-specific cellular neurophysiological responses to LB accumulation. Alternatively, it suggests that at least in EPM2b-/- mice, the neurobehavioral consequences of LB accumulation may not be observable within the typical lifespan of a laboratory mouse.
Funding:
VK is supported by NINDS K08NS110924 and seed funding from the BCM Office of Research.
Translational Research