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The Journal of Neuroscience, July 26, 2006, 26(30):7919-7932; doi:10.1523/JNEUROSCI.1674-06.2006

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Behavioral/Systems/Cognitive
MuSK Expressed in the Brain Mediates Cholinergic Responses, Synaptic Plasticity, and Memory Formation

Ana Garcia-Osta,¹ Panayiotis Tsokas,^3 * Gabriella Pollonini,^1 * Emmanuel M. Landau,^2,3,4 Robert Blitzer,³ and Cristina M. Alberini^1,2

Departments of ¹Neuroscience, ²Psychiatry, and ³Pharmacology, Mount Sinai School of Medicine, New York, New York 10029, and ⁴Psychiatry Service, Bronx Veterans Affairs Medical Center, Bronx, New York 10468

Correspondence should be addressed to Cristina M. Alberini, Department of Neuroscience, Box 1065, Mount Sinai School of Medicine, New York, NY 10029. Cristina.Alberini{at}mssm.edu

Muscle-specific tyrosine kinase receptor (MuSK) has been believed to be mainly expressed and functional in muscle, in which it mediates the formation of neuromuscular junctions. Here we show that MuSK is expressed in the brain, particularly in neurons, as well as in non-neuronal tissues. We also provide evidence that MuSK expression in the hippocampus is required for memory consolidation, because temporally restricted knockdown after training impairs memory retention. Hippocampal disruption of MuSK also prevents the learning-dependent induction of both cAMP response element binding protein (CREB) phosphorylation and CCAAT enhancer binding protein (C/EBP) expression, suggesting that the role of MuSK during memory consolidation critically involves the CREB–C/EBP pathway. Furthermore, we found that MuSK also plays an important role in mediating hippocampal oscillatory activity in the theta frequency as well as in the induction and maintenance of long-term potentiation, two synaptic responses that correlate with memory formation. We conclude that MuSK plays an important role in brain functions, including memory formation. Therefore, its expression and role are broader than what was believed previously.

Key words: MuSK; brain; long-term plasticity; memory; oscillatory response; C/EBP

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Received April 19, 2006; revised June 15, 2006; accepted June 16, 2006.

Correspondence should be addressed to Cristina M. Alberini, Department of Neuroscience, Box 1065, Mount Sinai School of Medicine, New York, NY 10029. Cristina.Alberini{at}mssm.edu

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