Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse.
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.
Roumier
Anne
A
Laboratoire 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.
Béchade
Catherine
C
Poncer
Jean-Christophe
JC
Smalla
Karl-Heinz
KH
Tomasello
Elena
E
Vivier
Eric
E
Gundelfinger
Eckart D
ED
Triller
Antoine
A
Bessis
Alain
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D017628:Microglia / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D017966:Pyramidal Cells / Q000502:physiology; D020813:Receptor, trkB / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C484963:Tyrobp protein, mouse; D020813:Receptor, trkB