Expression and properties of neuronal MHC class I molecules in the brain of the common marmoset monkey

Abstract

Several recent studies have highlighted the important role of immunity-related molecules in synaptic plasticity processes in the developing and adult rodent brain. It has been suggested that neuronal MHC (major histocompatibility complex) class I genes play a role in the refinement and pruning of synapses in the developing visual system and in certain forms of plasticity in the hippocampus. The aim of this study was to investigate the expression pattern and levels of MHC class I (MHCI) molecules throughout the development of the visual system and the hippocampus in a nonhuman primate, the common marmoset (Callithrix jacchus). The first part of this thesis describes expression of MHCI molecules in the visual cortex of the common marmoset monkey. Analysis of the neurons of the marmoset visual cortex revealed high levels of expression of MHCI genes very early in postnatal development, at a stage when synaptogenesis takes place and ocular dominance columns are formed. To determine whether MHC class I gene expression levels are regulated by retinal activity, animals were subjected to monocular enucleation, which is a method known to induce an ocular dominance shift in the visual cortex. MHC class I mRNA expression was higher in response to monocular enucleation. Furthermore, MHC class I immunoreactivity revealed variations in staining intensity of layer IV neurons in the visual cortex of enucleated animals, which was not observed in control animals. The pattern of MHC class I immunoreactivity indicated that higher expression levels were associated with retinal activity coming from the intact eye. These observations demonstrate that, in the primate brain, neuronal MHC class I gene expression is regulated by neuronal activity. Moreover, they extend previous findings by suggesting a role for neuronal MHC class I molecules during synaptogenesis in the visual cortex. The second part of the thesis describes expression of MHCI molecules in the hippocampal formation. MHCI mRNA is present at high levels in all subregions of the hippocampus (in dentate gyrus, hilus and areas CA1-CA3). However, a presynaptic, mossy-fiber-specific localization of MHCI proteins within the marmoset hippocampus was observed. MHCI molecules are present in the large VGlut1-positive mossy-fiber terminals, which provide input to CA3 pyramidal neurons. Furthermore, whole-cell recordings of CA3 pyramidal neurons in acute hippocampal slices of the common marmoset demonstrated that application of antibodies which specifically block MHCI proteins caused a significant decrease in the frequency and a transient increase in the amplitude of sEPSCs (spontaneous excitatory postsynaptic currents) in CA3 pyramidal neurons. These findings allude to a role of MHCI molecules in plasticity processes at the primate mossy fiber-CA3 synapses. Taken together, the present thesis describes in detail expression of MHCI molecules in the common marmoset visual system and the hippocampus. Furthermore, it extends previous studies in other model animals by implicating neuronal MHCI in synaptogenesis in the visual cortex and in the plasticity of the hippocampal mossy fiber synapses.