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Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in
Vaishnav Krishnan1, Jun Wu2, Arindam Ghosh Mazumder1
1Department of Neurology, Peter Kellaway Section of Neurophysiology and Epilepsy, Baylor College of Medicine, Houston, Texas, USA.
The Journal of Comparative Neurology
|July 23, 2024
Summary
Lafora disease mouse models show Lafora body accumulation without immediate behavioral changes, suggesting a treatment window before significant neurodegeneration occurs.
Area of Science:
- Neuroscience
- Genetics
- Epilepsy Research
Background:
- Lafora disease (LD) is a fatal neurodegenerative disorder characterized by myoclonic epilepsy and cognitive decline.
- It results from genetic mutations affecting EPM2A (laforin) or NHLRC1 (malin), leading to Lafora body (LB) accumulation in neurons and astrocytes.
- Current understanding suggests LB buildup directly causes neurological symptoms.
Purpose of the Study:
- To investigate neurobehavioral changes in malin-deficient LD mice using home-cage monitoring.
- To identify reliable preclinical endpoints for evaluating novel genetic therapies for Lafora disease.
- To explore the relationship between LB accumulation and neurobehavioral deterioration.
Main Methods:
- Home-cage monitoring of malin-deficient (KO) and wild-type (WT) mice at multiple ages (6 weeks, 6-7 months, 12 months).
- Assessment of rest/arousal, consumptive behaviors, risk aversion, and wheel-running activity.
- Neuropathological examination, electroencephalography (EEG), in vitro neocortical slice electrophysiology, and pentylenetetrazole (PTZ) seizure response testing.
Main Results:
- No significant behavioral differences were observed between KO and WT mice in home-cage monitoring across all timepoints.
- Age-dependent LB accumulation, gliosis, and microglial activation were confirmed in KO mice.
- In vitro assays revealed prolonged network bursts in KO slices at younger ages and increased seizure susceptibility to PTZ, despite normal EEG in vivo.
- A dissociation between LB burden and overt behavioral deficits was evident.
Conclusions:
- Lafora body accumulation in malin-deficient mice precedes significant, detectable neurobehavioral deterioration.
- Home-cage monitoring may not be sensitive enough to detect early-stage LD in this model.
- A potential therapeutic window exists between LB accumulation and the onset of clinical symptoms, warranting further investigation into early intervention strategies.
