TY - JOUR T1 - The Impact of Electrographic Seizures on Developing Hippocampal Dendrites Is Calcineurin Dependent JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0014-17.2017 SP - ENEURO.0014-17.2017 AU - Masataka Nishimura AU - J.R. Casanova AU - John W. Swann Y1 - 2017/04/21 UR - http://www.eneuro.org/content/early/2017/04/21/ENEURO.0014-17.2017.abstract N2 - Neurobehavioral abnormalities are commonly associated with intractable childhood epilepsy. Studies from numerous labs have demonstrated cognitive and socialization deficits in rats and mice that have experienced early-life seizures. However, the cellular and molecular mechanisms underlying these effects are unknown. Previously, experiments have shown that recurrent seizures in infancy suppress the growth of hippocampal dendrites at the same time they impair learning and memory. Experiments in slice cultures have also demonstrated dendrite growth suppression. Here, we crossed calcineurin B1 (CaNB1) floxed and Thy1GFP-M mice to produce mice that were homozygous for the both the floxed calcineurin B1 and the Thy1GFP-M transgene. Littermates that were homozygous for wild type calcineurin B1 and Thy1GFP-M served as controls. Hippocampal slice cultures from these mice were transfected with an AAV/hSyn-mCherry-Cre virus to eliminate calcineurin B1 from neurons. Immunohistochemical results showed that CaNB1 was eliminated from at least 90% of the transfected CA1 pyramidal cells. Moreover, the calcineurin-dependent nuclear translocation of the CREB transcription co-activator, CRTC1 was blocked in transfected neurons. Cell attach patch recordings combined with live multiphoton imaging demonstrated that the loss of CaNB1 did not prevent neurons from fully participating in electrographic seizure activity. Finally, dendrite reconstruction showed that the elimination of CaNB1 prevented seizure-induced decreases in both dendrite length and branch number. Results suggest that calcineurin plays a key role in seizure-induced dendrite growth suppression and may contribute to the neurobehavioral co-morbidities of childhood epilepsy.Significance Statement Seizures are thought to have a negative impact on the developing brain. This is particularly true for the epileptic encephalopathies that are commonly characterized by recurring seizures that are unresponsive to medication. Neurobehavioral abnormalities, including intellectual disabilities, are frequent in these patient populations. Research in numerous animal models has been able to reproduce many aspects of these clinical syndromes including learning and memory deficits. However, the cellular and molecular mechanisms contributing to cognitive decline are only now beginning to be revealed. In in vitro experiments reported here, we extend our studies of seizure-induced abnormalities in developing hippocampal dendrites and show that the calcium calmodulin dependent protein phosphatase, calcineurin plays a key role in electrographic seizure-induced reductions in dendrite length and branching complexity. ER -