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The Journal of Neuroscience, September 1, 2000, 20(17):6459-6472

Impaired Synaptic Plasticity and cAMP Response Element-Binding Protein Activation in Ca²⁺/Calmodulin-Dependent Protein Kinase Type IV/Gr-Deficient Mice

Nga Ho¹, Jason A. Liauw², Frank Blaeser¹, Feng Wei², Silva Hanissian⁷, Lisa M. Muglia¹, David F. Wozniak³, Anthony Nardi³, Kara L. Arvin¹, David M. Holtzman⁴, David J. Linden⁸, Min Zhuo², Louis J. Muglia^{1, 5}, and Talal A. Chatila^{1, 6}

Departments of ¹ Pediatrics, ² Anesthesiology, Anatomy and Neurobiology, ³ Psychiatry, ⁴ Neurology, and the Center for the Study of Nervous System Injury, ⁵ Molecular Biology and Pharmacology and Obstetrics and Gynecology, and ⁶ Pathology and Immunology, and the Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, ⁷ Division of Immunology/Rheumatology, The Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, and ⁸ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The Ca²⁺/calmodulin-dependent protein kinase type IV/Gr (CaMKIV/Gr) is a key effector of neuronal Ca²⁺ signaling; its function was analyzed by targeted gene disruption in mice. CaMKIV/Gr-deficient mice exhibited impaired neuronal cAMP-responsive element binding protein (CREB) phosphorylation and Ca²⁺/CREB-dependent gene expression. They were also deficient in two forms of synaptic plasticity: long-term potentiation (LTP) in hippocampal CA1 neurons and a late phase of long-term depression in cerebellar Purkinje neurons. However, despite impaired LTP and CREB activation, CaMKIV/Gr-deficient mice exhibited no obvious deficits in spatial learning and memory. These results support an important role for CaMKIV/Gr in Ca²⁺-regulated neuronal gene transcription and synaptic plasticity and suggest that the contribution of other signaling pathways may spare spatial memory of CaMKIV/Gr-deficient mice.

Key words: calcium/calmodulin-dependent kinase; synaptic plasticity; LTP; LTD; CREB; memory

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20176459-14$05.00/0

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