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

Abstract

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.

Developmental Regulation of TREM2 and DAP12 Expression in the Murine CNS: Implications for Nasu-Hakola Disease

“…Furthermore, we reported that in the healthy adult murine CNS, only subsets of microglia expressed Trem2 mRNA as assayed by in situ hybridization analysis [15]. However, in vitro studies indicated the potential for oligodendrocytes to express Trem2 and DAP12 while DAP12KO mice were observed to display modest myelin abnormalities [19][20][21][22]. Here we directly characterize microglial and oligodendrocyte expression of Trem2 and DAP12 by dual immunohistochemistry/in situ hybridization analysis during post-natal period of oligodendrocyte development and myelination.…”

“…First, histological analysis of adult CNS tissue from DAP12 knock-out mice in studies by two separate groups revealed modest, diffuse hypomyelination in anterior brain regions that was associated with substantial reductions in CNS microglia [20][21][22]. Subsequent gene profiling studies of CNS mRNA isolated from DAP12KO mice by a third group revealed decreased expression of selected myelin transcripts [23].…”

KARAP/DAP12/TYROBP: three names and a multiplicity of biological functions

“…This discrepancy could relate to different experimental culture conditions. Finally, impaired synaptic function has been reported in the brain of KARAP/DAP12-deficient mice, correlating KARAP/DAP12 deficiency with both histological and functional brain alterations [53].…”

“…The KARAP/DAP12-dependent mechanisms responsible for this brain pathology are still unknown. KARAP/DAP12 expression is detectable in human and mouse brain, in particular in microglial cells [46,51,53]. Controversial data have been published regarding KARAP/DAP12 expression in in-vitro-cultured oligodendrocytes, cells primarily involved in the production of myelin sheath [50,51,53].…”

The ecology of brain tumors: lessons learned from neurofibromatosis-1

“…Tumor-associated microglia constitute the main population of brain immune cells (Graeber et al, 2002) and are important for monitoring their local environment, regulating function and apoptosis, and secreting proinflammatory cytokines (Banati et al, 1993;Elkabes et al, 1996;Marı´n-Teva et al, 2004;Roumier et al, 2004). These resident brain immune system mononuclear cells can be recruited by glioma tumors cells to the local tumor microenvironment by vascular Figure 3 Co-evolution of neoplastic and non-neoplastic cells in gliomas.…”