Seizure-induced LIN28A disrupts pattern separation via aberrant hippocampal neurogenesis

Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of pilocarpine-induced status epilepticus (SE), we characterized spatiotemporal expression of Lin28a mRNA and proteins after SE. Unlike Lin28a transcripts, induction of LIN28A protein after SE was detected mainly in the subgranular zone, where immunoreactivity was found in progenitors, neuroblasts, and immature and mature granule neurons. To investigate roles of LIN28A in epilepsy, we generated Nestin-Cre::Lin28aloxP/loxP (cKO) and Nestin-Cre::Lin28a+/+ (WT) mice to block LIN28A upregulation in all neuronal lineages after acute seizure. Adult-generated neuron- and hippocampus-associated cognitive impairments were absent in epileptic LIN28A cKO mice as evaluated by pattern separation and contextual fear conditioning tests, respectively, while sham-manipulated WT and cKO animals showed comparable memory function. Moreover, numbers of hilar PROX1-expressing ectopic granule cells (EGCs), together with PROX1/NEUN+ mature EGCs, were significantly reduced in epileptic cKO mice. Transcriptomic analysis and immunohistochemical validation at 3 d post-pilocarpine provided potential LIN28A downstream targets such as serotonin receptor 4. Collectively, our findings indicate that LIN28A is a novel target for regulation of newborn neuron-associated memory dysfunction in epilepsy by modulating seizure-induced aberrant neurogenesis. Overall design: To investigate the function of LIN28A in epilepsy-associated cognitive impairment, we generated Nestin-Cre::LIN28A loxP wildtype and conditional knockout mice. We then subjected these mice to sham- or pilocarpine-induced status epilepticus.