Deletion of the N-terminus of murine MAP2 by gene targeting disrupts hippocampal CA1 neuron architecture and alters contextual memory

Z. Khuchua, D. F. Wozniak, M. E. Bardgett, Z. Yue, M. McDonald, J. Boero, R. E. Hartman, H. Sims, A. W. Strauss

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Microtubule-associated protein-2 (MAP2) is a brain specific A-kinase anchoring protein that targets the cyclic AMP-dependent protein kinase holoenzyme (PKA) to microtubules. Phosphorylation of MAP2 by different protein kinases is crucial for neuronal growth. The N-terminus of MAP2 contains the binding site for regulatory subunit II of cAMP-dependent protein kinase (PKA-RIIβ). Using homologous recombination, we created a mutant line of mice (Δ1-158) that express truncated MAP2 lacking the N-terminal peptide and the PKA binding site. Deletion of the PKA binding site from the MAP2 gene resulted in decreased efficiency of MAP2 phosphorylation. Biochemical and immunohistochemical studies demonstrate major changes in the morphology of hippocampal neurons in Δ1-158 mice. Behavioral tests indicate that Δ1-158 mice were impaired (exhibited less conditioned freezing) relative to Wild-Type (WT) controls during a test of contextual, but not during auditory cue, fear conditioning when tested at 8 weeks or 8 months of age. The Δ1-158 mice displayed a heightened sensitivity to shock at 8 weeks, but not at 8 months of age. We conclude that PKA binding to MAP2 and MAP2 phosphorylation is essential for the selective development of contextual memory.

Original languageEnglish
Pages (from-to)101-111
Number of pages11
JournalNeuroscience
Volume119
Issue number1
DOIs
StatePublished - Jun 18 2003

Keywords

  • CAMP
  • Cytoskeleton
  • Hippocampus
  • PKA
  • Signal transduction

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