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Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age\u2010dependent manner in all mouse models of LD. In this study, we applied home\u2010cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin\u2010deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, \u223c6\u20137 months, and \u223c12 months of age, malin\u2010deficient mice (\u201cKO\u201d) and wild\u2010type (WT) littermates underwent a standardized home\u2010cage behavioral assessment designed to non\u2010obtrusively appraise features of rest\/arousal, consumptive behaviors, risk aversion, and voluntary wheel\u2010running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age\u2010related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel\u2010running. Neuropathological examinations in subsets of the same mice revealed expected age\u2010dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home\u2010cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.<\/jats:p>","DOI":"10.1002\/cne.25660","type":"journal-article","created":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T03:42:48Z","timestamp":1721706168000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home\u2010Cage Behavior"],"prefix":"10.1002","volume":"532","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2847-0069","authenticated-orcid":false,"given":"Vaishnav","family":"Krishnan","sequence":"first","affiliation":[{"name":"Department of Neurology, Peter Kellaway Section of Neurophysiology and Epilepsy Baylor College of Medicine  Houston Texas 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