These convergent ties between NEAT1 and epilepsy led us to speculate that our results may thus provide a mechanistic basis for these associations and explain how NEAT1 could drive excessive cortical neuronal activity characteristic of epilepsy26. However, since we found that knockdown of NEAT1 increased neuronal excitability (Fig. 2b), it was initially unclear why NEAT1 should be up-regulated in seizure patient brains. To explain this apparent discrepancy, we hypothesized that NEAT1 expression changes may vary according to temporal stimulation. To investigate this hypothesis, we employed in vivo rat models of chronic seizures. First, we found that acute (1 and 7 days) pilocarpine-induced seizure activity, a well-established model of temporal lobe epilepsy [TLE27], significantly down-regulated NEAT1 expression (Fig. 4c), consistent with our findings in iPSC-derived neurons where NEAT1 was also down-regulated upon acute stimulation. However, after one month, seizure-dependent NEAT1 down-regulation in response to chronic pilocarpine-induced seizure activity interestingly disappeared (Fig. 4c), perhaps due to homeostatic feedback. Second, we employed the hippocampal-specific kainic acid-induced seizure rat model that also closely resembles features of TLE28. Here, we again saw an acute (24
