Hyperexcitability and epileptic seizures in a model of frontotemporal dementia

Abstract

Epileptic seizures are more common in patients with Alzheimer disease than in the general elderly population. Abnormal forms of hyperphosphorylated tau accumulate in Alzheimer disease and other tauopathies. Aggregates of tau are also found in patients with epilepsy and in experimental models of epilepsy. We report here the analysis of epileptic activity and neuropathological correlates of a transgenic line over-expressing human mutant tau, a model of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The FTDP-17 model displays spontaneous epileptic activity and seizures with spike-wave complexes in the EEG, and a higher sensitivity to the GABAA receptor antagonist pentylenetetrazol (PTZ) when compared to age-matched controls, showing a notably increased seizure length and a shorter latency to develop severe seizures. FTDP-17 human tau mutants also display lower convulsive thresholds and higher lethality after PTZ injections. Astrocytosis and activated microglia are prominent in the hippocampus and other brain regions of young FTDP-17 mice where the human mutant tau transgene is expressed, before the appearance of hyperphosphorylated tau aggregates in these structures. FTDP-17 human mutant tau over-expression produces epilepsy and increased GABAA receptor-mediated hyperexcitability in the absence of Aβ pathology. Although aggregates of hyperphosphorylated tau have been observed in patients with epilepsy and in different chemically and electrically generated models of epilepsy, the FTDP-17 tau mutant analyzed here is the first model of genetically modified tau that presents with epilepsy. This model may represent a valuable tool to assay novel treatments in order to reduce tau pathology, a potential factor which may be involved in the development of epileptic seizures in dementia and other neurodegenerative diseases.

Keywords: AD; APP; Alzheimer disease; Astrocytosis; Aβ; Chemoconvulsant; EEG; Epilepsy; FTDP-17; FTDP-17 tau mutations; GL; Human Tau(VLW); Hyperphosphorylated tau aggregates; ML; Microgliosis; NFTs; PTZ; Psen; amyloid precursor protein; amyloid-β; electroencephalography; frontotemporal dementia with parkinsonism linked to chromosome 17; granular layer of the hippocampus; molecular layer of the hippocampus; neurofibrillary tangles; pentylenetetrazol; presenilin; transgene of human tau isoform with 2 N-terminal inserts, 4-microtubule-binding-repeat elements and with G272V (V), P301L (L), and R406W (W) mutations under the control of the neuron-specific Thy-1 promoter.