Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: A study with knockout mice

Involvement of neurogranin in the modulation of calcium/calmodulin-dependent protein kinase II, synaptic plasticity, and spatial learning: A study with knockout mice

^†Endocrinology and Reproduction Research Branch and ^**Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and ^§Department of Neurophysiology and ^¶Project Group Neuropharmacology, Leibniz Institute for Neurobiology, D-39008 Magdeburg, Germany

Edited by Louis Sokoloff, National Institutes of Health, Bethesda, MD, and approved August 11, 2000 (received for review April 24, 2000)

Abstract

Neurogranin/RC3 is a neural-specific Ca²⁺-sensitive calmodulin (CaM)-binding protein whose CaM-binding affinity is modulated by phosphorylation and oxidation. Here we show that deletion of the Ng gene in mice did not result in obvious developmental or neuroanatomical abnormalities but caused an impairment of spatial learning and changes in hippocampal short- and long-term plasticity (paired-pulse depression, synaptic fatigue, long-term potentiation induction). These deficits were accompanied by a decreased basal level of the activated Ca²⁺/CaM-dependent kinase II (CaMKII) (≈60% of wild type). Furthermore, hippocampal slices of the mutant mice displayed a reduced ability to generate activated CaMKII after stimulation of protein phosphorylation and oxidation by treatments with okadaic acid and sodium nitroprusside, respectively. These results indicate a central role of Ng in the regulation of CaMKII activity with decisive influences on synaptic plasticity and spatial learning.

Footnotes

↵ * J.H.P. and F.L.H. contributed equally to this work.
↵ ‡ Present address: Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
↵ ‖ Present address: Department of Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232.
↵ ‡‡ To whom reprint requests should be addressed. E-mail: kphuang{at}helix.nih.gov.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF230869).
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.210184697.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.210184697
Abbreviations:

Ng,

neurogranin/RC3;

CaM,

calmodulin;

PKC,

protein kinase C;

WT,

wild type;

KO,

knockout;

HET,

heterozygote/heterozygous;

CaMKII,

calmodulin-dependent protein kinase II;

Nm,

neuromodulin/GAP-43;

LTP,

long-term potentiation;

SNP,

sodium nitroprusside;

IPI,

interpulse interval;

PPD,

paired-pulse depression;

fEPSP,

field excitatory postsynaptic potential;

PPF,

paired-pulse facilitation;

X-gal,

5-bromo-4-chloro-3-indolyl β-d-galactoside