The Impact of Electrographic Seizures on Developing Hippocampal Dendrites Is Calcineurin Dependent.
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 CaNB1 and the Thy1GFP-M transgene. Littermates that were homozygous for wild-type CaNB1 and Thy1GFP-M served as controls. Hippocampal slice cultures from these mice were transfected with an AAV/hSyn-mCherry-Cre virus to eliminate CaNB1 from neurons. Immunohistochemical results showed that CaNB1 was eliminated from at least 90% of the transfected CA1 pyramidal cells. Moreover, the CaN-dependent nuclear translocation of the CREB transcription coactivator, CREB-regulated transcriptional coactivator 1 (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 CaN plays a key role in seizure-induced dendrite growth suppression and may contribute to the neurobehavioral comorbidities of childhood epilepsy.
['Nishimura|Masataka|M|', 'Casanova|J R|JR|', 'Swann|John W|JW|']
D048868:Adaptor Proteins, Signal Transducing D000818:Animals D019703:Calcineurin D003712:Dendrites D004195:Disease Models, Animal D006624:Hippocampus D047908:Intracellular Signaling Peptides and Proteins D007858:Learning D008568:Memory D051379:Mice D009474:Neurons D010750:Phosphoproteins D017966:Pyramidal Cells D012640:Seizures
development epilepsy FK506 fCaNB1 hippocampus viral transfections