In vivo glutamate clearance defects in a mouse model of Lafora disease

Abstract

Lafora disease (LD) is a fatal rare neurodegenerative disorder characterized by epilepsy, neurodegeneration and insoluble polyglucosan accumulation in brain and other peripheral tissues. Although in the last two decades we have increased our knowledge on the molecular basis underlying the pathophysiology of LD, only a small part of the research in LD has paid attention to the mechanisms triggering one of the most lethal features of the disease: epilepsy. Recent studies in our laboratory suggested that a dysfunction in the activity of the mouse astrocytic glutamate transporter 1 (GLT-1) could contribute to epilepsy in LD. In this work, we present new in vivo evidence of a GLT-1 dysfunction, contributing to increased levels of extracellular glutamate in the hippocampus of a mouse model of Lafora disease (Epm2b−/−, lacking the E3-ubiquitin ligase malin). According to our results, Epm2b−/− mice showed an increased neuronal activity, as assessed by c-fos expression, in the hippocampus, an area directly correlated to epileptogenesis. This brain area presented lesser ability to remove synaptic glutamate after local GLT-1 blockade with dihydrokainate (DHK), in comparison to Epm2b+/+ animals, suggesting that these animals have a compromised glutamate clearance when a challenging condition was presented. These results correlate with a hippocampal upregulation of the minor isoform of the Glt-1 gene, named Glt-1b, which has been associated with compensatory mechanisms activated in response to neuronal stress. In conclusion, the hippocampus of Epm2b−/− mice presents an in vivo impairment in glutamate uptake which could contribute to epileptogenesis.