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ISDN2014_0096: Effects of PQQ on cognitive function induced by MK801 and its molecular imaging evaluation
Author(s) -
Zhou X.Q.,
Chen Q.C.,
Mao S.S.,
Qin X.F.,
Xu X.J.,
Kong Y.Y.
Publication year - 2015
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2015.04.078
Subject(s) - christian ministry , medicine , nuclear medicine , political science , law
cus, correlate with a higher risk of developing cognitive deficits and temporal lobe epilepsy as adults, suggesting that they may permanently change the developmental trajectory of neuronal circuits. The mechanisms underlying these effects are not clear. Cationchloride cotransporter KCC2 decreases intracellular Cl− levels and renders GABA responses hyperpolarizing. Recent data suggest that KCC2 also modulates excitatory synapse development. Here, we demonstrated that KCC2 expression is altered by early-life febrile status epilepticus and investigated the functional impact of this alteration on subsequent synapse formation. We analyzed KCC2 expression and spine density in the hippocampus of a well-established rodent model of atypical febrile seizures, combining a cortical freeze lesion at post-natal day 1 (P1) and hyperthermia-induced seizure at P10 (LHS rats). At P20, we found a precocious increase in KCC2 protein levels, accompanied by a negative shift of Egaba following high-frequency stimulation. In parallel, we observed a striking reduction in dendritic spine density and of mEPSC amplitude and frequency in CA1 pyramidal neurons. To investigate whether KCC2 precocious overexpression plays a role in spine alterations, we mimicked it in hippocampal organotypic cultures by biolistic transfection and in-vivo by inutero electroporation. We found that both manipulations decreased spine density. Finally, to causally link KCC2 increased expression to spine loss in the LHS model, we blocked KCC2 in vivo by in utero electroporation of shRNA, and induced the dual pathologies as explained above. Our preliminary results suggest that reducing KCC2 expression levels in LHS rats rescued spine density loss. Therefore, increased KCC2 levels induced by early-life seizure affect spine formation and may be a contributing factor to the occurrence of hippocampal atrophy and associated cognitive deficits.