When tau goes electric: The first report of a positive correlation between tau burden and ex vivo hyperexcitability in human epileptic hippocampal slices

Neurodegeneration-associated proteins (NAPs) have been detected in the resected hippocampal tissue of patients with drug-resistant epilepsy. Given the lack of direct ex vivo correlation data in humans, our aim was to investigate the relationship between NAPs and hyperexcitability using human epileptic hippocampal slices. Spontaneous and 4-aminopyridine (4AP)-induced electrical activity was recorded in human hippocampal slices of 26 consecutive patients (16 females) with drug-resistant mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE/HS) using the multielectrode array technique. Parallel immunohistochemical NAPs staining was performed. Ex vivo electrical activity was successfully recorded in 73% of the samples (female/male: 12/7 samples, 58/29 slices). The median spike frequency, number of active electrodes, and global synchrony index were, respectively, 0.066/0.093 Hz, 4/11, and 0.337/0.694 in female samples, and 0.040/0.059 Hz, 3/6, and 0.344/0.673 in male samples during spontaneous/4AP-induced activity. Regarding NAPs, only deposits of hyperphosphorylated tau (p-tau) were detected. While no correlation between the spike frequency and p-tau was apparent during spontaneous firing, a positive correlation between these variables was observed during 4AP-induced activity (P = 0.0220) and concerning reactivity to the 4AP effect (P = 0.0084), the latter being different in female and male samples (P = 0.0451). No other sex differences were detected. We conclude that a positive correlation exists between p-tau and neuronal network hyperexcitability in human MTLE/HS hippocampal slices. This new finding suggests a role for the p-tau burden in the pathogenesis of drug-resistant MTLE/HS and highlights its potential to become a candidate for novel therapeutic strategies in this devastating disease.