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The Journal of Neuroscience, December 15, 2004, 24(50):11421-11428; doi:10.1523/JNEUROSCI.2251-04.2004

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Development/Plasticity/Repair
Impaired Synaptic Function in the Microglial KARAP/DAP12-Deficient Mouse

Anne Roumier,^1 * Catherine Béchade,^1 * Jean-Christophe Poncer,^2 * Karl-Heinz Smalla,³ Elena Tomasello,⁴ Eric Vivier,⁴ Eckart D. Gundelfinger,³ Antoine Triller,¹ and Alain Bessis¹

¹Laboratoire de Biologie Cellulaire de la Synapse Normale et Pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM) U497, Ecole Normale Supérieure, 75230 Paris Cedex 05, France, ² INSERM EMI0224, Cortex and Epilepsie, 75013 Paris, France, ³Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany, and ⁴Centre d'Immunologie INSERM-Centre National de la Recherche Scientifique de Marseille-Luminy, 13288 Marseille Cedex 09, France

Several proteins are expressed in both immune and nervous systems. However, their putative nonimmune functions in the brain remain poorly understood. KARAP/DAP12 is a transmembrane polypeptide associated with cell-surface receptors in hematopoeitic cells. Its mutation in humans induces Nasu-Hakola disease, characterized by presenile dementia and demyelinization. However, alteration of white matter occurs months after the onset of neuropsychiatric symptoms, suggesting that other neuronal alterations occur in the early phases of the disease. We hypothesized that KARAP/DAP12 may impact synaptic function. In mice deficient for KARAP/DAP12 function, long-term potentiation was enhanced and was partly NMDA receptor (NMDAR) independent. This effect was accompanied by changes in synaptic glutamate receptor content, as detected by the increased rectification of AMPA receptor EPSCs and increased sensitivity of NMDAR EPSCs to ifenprodil. Biochemical analysis of synaptic proteins confirmed these electrophysiological data. In mutants, the AMPA receptor GluR2 subunit expression was decreased only in the postsynaptic densities but not in the whole membrane fraction, demonstrating specific impairment of synaptic receptor accumulation. Alteration of the BNDF-tyrosine kinase receptor B (TrkB) signaling in the mutant was demonstrated by the dramatic decrease of synaptic TrkB with no change in other regulatory or scaffolding proteins. Finally, KARAP/DAP12 was detected only in microglia but not in neurons, astrocytes, or oligodendrocytes. KARAP/DAP12 may thus alter microglial physiology and subsequently synaptic function and plasticity through a novel microglia-neuron interaction.

Key words: synapse; microglia; LTP; glutamate receptor; BDNF; hippocampus; postsynaptic density

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Received June 9, 2004; revised November 5, 2004; accepted November 7, 2004.

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