title: LIMK1 regulates long-term memory and synaptic plasticity via the transcriptional factor CREB.
abstract: Deletion of the LIMK1 gene is associated with Williams syndrome, a unique neurodevelopmental disorder characterized by severe defects in visuospatial cognition and long-term memory (LTM). However, whether LIMK1 contributes to these deficits remains elusive. Here, we show that LIMK1-knockout (LIMK1(-/-)) mice are drastically impaired in LTM but not short-term memory (STM). In addition, LIMK1(-/-) mice are selectively defective in late-phase long-term potentiation (L-LTP), a form of long-lasting synaptic plasticity specifically required for the formation of LTM. Furthermore, we show that LIMK1 interacts and regulates the activity of cyclic AMP response element-binding protein (CREB), an extensively studied transcriptional factor critical for LTM. Importantly, both L-LTP and LTM deficits in LIMK1(-/-) mice are rescued by increasing the activity of CREB. These results provide strong evidence that LIMK1 deletion is sufficient to lead to an LTM deficit and that this deficit is attributable to CREB hypofunction. Our study has identified a direct gene-phenotype link in mice and provides a potential strategy to restore LTM in patients with Williams syndrome through the enhancement of CREB activity in the adult brain.
authors: Neurosciences & Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Zarko
authors: Z
authors: Todorovski
authors: Neurosciences & Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Suhail
authors: S
authors: Asrar
authors: Neurosciences & Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Jackie
authors: J
authors: Liu
authors: Neurosciences & Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Ner Mu Nar
authors: NM
authors: Saw
authors: Neurosciences & Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
authors: Krutika
authors: K
authors: Joshi
authors: Neurosciences & Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors: Miguel A
authors: MA
authors: Cortez
authors: Neurosciences & Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors: O Carter
authors: OC
authors: Snead
authors: The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China.
authors: Wei
authors: W
authors: Xie
authors: Neurosciences & Mental Health Program, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada zhengping.jia@sickkids.ca.
authors: Zhengping
authors: Z
authors: Jia
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism*; D017774:Long-Term Potentiation; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism; D057567:Memory, Long-Term; D008570:Memory, Short-Term; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D060066:Protein Interaction Maps; D018980:Williams Syndrome / Q000235:genetics / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D017362:Cyclic AMP Response Element-Binding Protein; D054461:Lim Kinases; C515893:Limk1 protein, mouse
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