RESUMO
Long-term memory (LTM) formation requires de novo gene expression in neurons, and subsequent structural and functional modification of synapses. However, the importance of gene expression in glia during this process has not been well studied. In this report, we characterize a cell adhesion molecule, Klingon (Klg), which is required for LTM formation in Drosophila. We found that Klg localizes to the juncture between neurons and glia, and expression in both cell types is required for LTM. We further found that expression of a glial gene, repo, is reduced in klg mutants and knockdown lines. repo expression is required for LTM, and expression increases upon LTM induction. In addition, increasing repo expression in glia is sufficient to restore LTM in klg knockdown lines. These data indicate that neuronal activity enhances Klg-mediated neuron-glia interactions, causing an increase in glial expression of repo. Repo is a homeodomain transcription factor, suggesting that further downstream glial gene expression is also required for LTM.
Assuntos
Condicionamento Clássico/fisiologia , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica/fisiologia , Proteínas de Homeodomínio/metabolismo , Memória de Longo Prazo/fisiologia , Neuroglia/metabolismo , Animais , Moléculas de Adesão Celular/genética , Células Cultivadas , Sistema Nervoso Central/citologia , Condicionamento Clássico/efeitos dos fármacos , Cicloeximida/farmacologia , Drosophila , Proteínas de Drosophila/genética , Proteínas do Olho/genética , Feminino , Antagonistas de Hormônios/farmacologia , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Camundongos Transgênicos , Mifepristona/farmacologia , Mutação/genética , Neuroglia/efeitos dos fármacos , Neurônios/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA/fisiologiaRESUMO
Glial pathology is a causal contributor to the striatal neuronal dysfunction of Huntington's disease (HD). We investigate mutant HTT-associated changes in gene expression by mouse and human striatal astrocytes, as well as in mouse microglia, to identify commonalities in glial pathobiology across species and models. Mouse striatal astrocytes are fluorescence-activated cell sorted (FACS) from R6/2 and zQ175 mice, which respectively express exon1-only or full-length mHTT, and human astrocytes are generated either from human embryonic stem cells (hESCs) expressing full-length mHTT or from fetal striatal astrocytes transduced with exon1-only mHTT. Comparison of differential gene expression across these conditions, all with respect to normal HTT controls, reveals cell-type-specific changes in transcription common to both species, yet with differences that distinguish glia expressing truncated mHTT versus full-length mHTT. These data indicate that the differential gene expression of glia expressing truncated mHTT may differ from that of cells expressing full-length mHTT, while identifying a conserved set of dysregulated pathways in HD glia.