The success of axonal regeneration has been attributed to a co-operation between the severed neurons and the surrounding environment, including non-neuronal cells and the extracellular matrix. Important differences regarding the regeneration potential after injury have been described among inbred mice strains. To date, there is only limited knowledge of how such variation can be linked with the genetic background. It has recently been demonstrated that MHC class I molecules have an influence on the spinal cord synaptic plasticity elicited by a peripheral lesion, and the regenerative capacity following such a lesion. Therefore, in the present work we compared the MHC I expression after axotomy in three isogenic mice strains, namely C57BL/6J, Balb/cJ, and A/J, and investigated the fine ultrastructure of the synaptic elimination process that follows such lesion. The results show that C57BL/6J mice, that have a comparatively poor regenerative potential, display a lower upregulation of MHC I in the spinal cord, coupled with a slower synaptic stripping. On the other hand, A/J mice, which have been shown to have a stronger axonal regrowth potential, showed a clear upregulation of MHC I and a sharp acute loss of afferents, at 1 week after lesion. Our results suggest that a more prominent expression of MHC I in the first week after lesion may positively influence the regenerative outcome associated with a more effective axonal regrowth. © 2007 Wiley-Liss, Inc.622137148Aldskogius, H., Liu, L., Svensson, M., Glial responses to synaptic damage and plasticity (1999) J Neurosci Res, 1, pp. 33-41Arvidsson, U., Riedl, M., Elde, R., Meister, B., Vesicular acetylcholine transporter (VAChT) protein: A novel and unique marker for cholinergic neurons in the central and peripheral nervous systems (1997) J Comp Neurol, 378, pp. 454-467Baba, A., Role of endothelin B receptor signals in reactive astrocytes (1998) Life Sci, 62, pp. 1711-1715Barron, K.D., Axon reaction and central nervous system regeneration (1983) Nerve, organ and tissue regeneration: Research perspectives, pp. 3-36. , Seil FJ, editor, New York: Academic Press. pConnaughton, M., Priestley, J.V., Sofroniew, M.V., Eckenstein, F., Cuello, A.C., Inputs to motoneurones in the hypoglossal nucleus of the rat: Light and electron microscopic immunocytochemistry for choline acetyltransferase, substance P and enkephalins using monoclonal antibodies (1986) Neuroscience, 17, pp. 205-224Conradi, S., On motoneuron synaptology in adult cats (1969) Acta Physiol Scand, 332, pp. 1-57Corriveau, R.A., Huh, G.S., Shatz, C.J., Regulation of class I MHC gene expression in the developing and mature CNS by neural activity (1998) Neuron, 21, pp. 505-520Emirandetti, A., Zanon, R.G., Sabha Jr, M., De Oliveira, A.L., Astrocyte reactivity influences the number of presynaptic terminals apposed to spinal motoneurons after axotomy (2006) Brain Res, 1095, pp. 35-42Fawcett, J.W., Intrinsic neuronal determinants of regeneration (1992) Trends Neurosci, 15, pp. 5-8Foster, J.A., Quan, N., Stern, E.L., Kristensson, K., Herkenham, M., Induced neuronal expression of class I major histocompatibility complex mRNA in acute and chronic inflammation models (2002) J Neuroimmunol, 131, pp. 83-91Fujimaki, H., Hikawa, N., Nagoya, M., Nagata, T., Minami, M., IFN-γ induces expression of MHC class I molecules in adult mouse dorsal root ganglion neurones (1996) Neuroreport, 7, pp. 2951-2955Gimenez YRibotta, M., Menet, V., Privat, A., The role of astrocytes in axonal regeneration in the mammalian CNS (2001) Prog Brain Res, 132, pp. 587-610Graeber, M.B., Tetzlaff, W., Streit, W.J., Kreutzberg, G.W., Microglial cells but not astrocytes undergo mitosis following facial nerve axotomy (1988) Neurosci Lett, 85, pp. 317-321Huh, G.S., Boulanger, L.M., Du, H., Riquelme, P.A., Brotz, T.M., Shatz, C.J., Functional requirement for class I MHC in CNS development and plasticity (2000) Science, 290, pp. 2155-2159Lainetti, R.D., Pereira, F.C., Da-Silva, C.F., Reduced sensory motoneuron regeneration by C57BL/6J mice (1995) Br J Med Biol Res, 28, pp. 781-785Lampson, L.A., Fisher, C.A., Weak HLA and β2-microglobulin expression of neuronal cell lines can be modulated by interferon (1984) Proc Natl Acad Sci USA, 81, pp. 6476-6480Lidman, O., Fraidakis, M., Lycke, N., Olson, L., Olsson, T., Piehl, F., Facial nerve lesion responsestrain differences but no involvement of IFN-γ, STAT4 or STAT6 (2002) NeuroReport, 13, pp. 1589-1593Lindå, H., Piehl, F., Dagerlind, A., Verge, V.M., Arvidsson, U., Cullheim, S., Risling, M., Hokfelt, T., Expression of GAP-43 mRNA in the adult mammalian spinal cord under normal conditions and after different types of lesions, with special reference to motoneurons (1992) Exp Brain Res, 91, pp. 284-295Lindå, H., Hammarberg, H., Cullheim, S., Levinovitz, A., Khademi, M., Olsson, T., Expression of MHC class I and β2-microglobulin in rat spinal motoneurons: Regulatory influences by IFN-γ and axotomy (1998) Exp Neurol, 150, pp. 282-295Lindå, H., Shupliakov, O., Ornung, G., Ottersen, O.P., Storm-Mathisen, J., Risling, M., Cullheim, S., Ultrastructural evidence for a preferential elimination of glutamate-immunoreactive synaptic terminals from spinal motoneurons after intramedullary axotomy (2000) J Comp Neurol, 425, pp. 10-23Lu, X., Skamene, E., Richardson, P.M., Studies of axonal regeneration in C57BL/6J and A/J mice (1994) Brain Res, 652, pp. 174-176McLaughlin, B.J., Dorsal root projections to the motor nuclei in the cat spinal cord (1972) J Comp Neurol, 144, pp. 461-473Neumann, H., Cavalie, A., Jenne, D., Wekerle, H., Induction of MHC class I genes in neurons (1995) Science, 269, pp. 549-552Neumann, H., Schmidt, H., Cavalie, A., Jenne, D., Wekerle, H., Major histocompatibility complex (MHC) class I gene expressionin single neurons of the central nervous system: Differential regulation by interferon (IFN)-γ and tumor necrosis factor (TNF)-α (1997) J Exp Med, 185, pp. 305-316Oliveira, A.L.R., Apoptosis of sensory neurons and satellite cells after sciatic nerve transaction in C57BL/6J mice (2001) Braz J Med Biol Res, 34, pp. 375-380Oliveira, A.L.R., Langone, F., Non-neuronal cells are not the limiting factor for the low axonal regeneration in C57BL/6J (2000) Braz J Med Biol Res, 33, pp. 1467-1475Oliveira, A.L.R., Thams, S., Lidman, O., Piehl, F., Hökfelt, T., Kärre, K., Lindå, H., Cullheim, S., A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy (2004) Proc Natl Acad Sci USA, 101, pp. 17843-17848Ornung, G., Shupliakov, O., Ottersen, O.P., Storm-Mathisen, J., Cullheim, S., Immunohistochemical evidence for coexistence of glycine and GABA in nerve terminals on cat spinal motoneurones: An ultrastructural study (1994) Neuroreport, 14, pp. 889-892Pereira, R.A., Tscharke, D.C., Simmons, A., Upregulation of class I major histocompatibility complex mRNA in primary sensory neurons, satellite cells, and Schwann cells of mice in response to acute but not latent herpes simplex virus infection in vivo (1994) J Exp Med, 180, pp. 841-850Redwine, J.M., Buchmeier, M.J., Evans, C.F., In vivo expression of major histocompatibility complex molecules on oligodendrocytes and neurons during viral infection (2001) Am J Pathol, 159, pp. 1219-1224Shupliakov, O., Ornung, G., Brodin, L., Ulfhake, B., Ottersen, O.P., Storm-Mathisen, J., Cullheim, S., Immunocytochemical localization of amino acid neurotransmitter candidates in the ventral horn of the cat spinal cord: A light microscopic study (1993) Exp Brain Res, 96, pp. 404-418Streit, W.J., Kreutzberg, G.W., The response of endogenous glial cells to motor neuron degeneration induced by toxic ricin (1988) J Comp Neurol, 268, pp. 248-263Svensson, M., Aldskogius, H., Synaptic density of axotomized hypoglossal motorneurons following pharmacological blockade of the microglial cell proliferation (1993) Exp Neurol, 120, pp. 123-131Wekerle, H., Planting and pruning in the brain: MHC antigens involved in synaptic plasticity? (2005) Proc Natl Acad Sci USA, 102, pp. 3-4Wong, G.H., Bartlett, P.F., Clark-Lewis, I., Battye, F., Schrader, J.W., Inducable expression of H-2 and Ia antigens on brain cells (1984) Nature, 310, pp. 688-691Xin, L., Richardson, P.M., Gervais, F., Skamene, E., A deficiency of axonal regeneration in C57BL/6J mice (1990) Brain Res, 510, pp. 144-146Zanon, R.G., Oliveira, A.L.R., MHC I upregulation influences astroglial reaction and synaptic plasticity in the spinal cord after sciatic nerve transection (2006) Exp Neurol, 200, pp. 521-531