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Reducing astrocyte calcium signaling in vivo alters striatal microcircuits and causes repetitive behavior II

ABSTRACT: Astrocytes tile the central nervous system, but their functions in neural microcircuits in vivo and their roles in mammalian behavior remain incompletely defined. We used 2-photon laser scanning microscopy (2PLSM), electrophysiology, MINIscopes, RNA-seq and a new genetic approach to characterize the effects of reduced striatal astrocyte Ca2+ signaling in vivo. In wild type mice, reducing striatal astrocyte Ca2+-dependent signaling increased repetitive self-grooming behaviors by altering medium spiny neuron (MSN) activity. The mechanism involved astrocyte-mediated neuromodulation mediated by ambient GABA and was corrected by blocking astrocyte GABA transporter 3 (GAT-3). Furthermore, in a mouse model of Huntington’s disease, dysregulation of GABA and astrocyte Ca2+ signaling accompanied excessive self-grooming, which was relieved by blocking GAT-3. Assessments with RNA-seq revealed astrocyte genes and pathways regulated by Ca2+ signaling in a cell autonomous and non-cell autonomous manner, including Rab11a, a regulator of GAT-3 functional expression. Thus, striatal astrocytes contribute to neuromodulation controlling obsessive-compulsive-like behavior in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE114756 | GEO | 2019/05/09

REPOSITORIES: GEO

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Project description:One way by which astrocytes modulate oligodendrocytes’ activity is by delivering neurotransmitters and leukemia inhibitory factor (Lif) in the medium that bind oligodendrocyte receptors. Most of these receptors are involved in intercellular Ca2+-signaling (ICS). However, not much is known about the interactions between myelination (MYE) and ICS genes and how astrocyte nearness modulates the oligodendrocyte genomic myelination fabric. We profiled the transcriptomes of immortalized oligodendrocyte precursor cells (Oli-neu) when cultured alone or co-cultured with cortical astrocytes. The astrocytes were plated in cell culture insert systems that did not allow formation of gap junction channels with oligodendrocytes but permitted exchange of soluble factors via the culture medium. Remarkably, astrocyte proximity induced a larger increase of the overall expression level and interlinkage of MYE genes than the differentiating 10d treatment with 1 mM dibutyryl cAMP that turns Oli-neu cells into myelin-associated glycoprotein-positive oligodendrocyte-like cells. Moreover, more MYE and ICS genes were turned on and fewer turned off by astrocyte proximity than by differentiating treatment. Lif receptor was up-regulated by astrocyte proximity but not by the differentiating treatment. We have identified the responsible transcriptomic networks by which the intercellular ICS gene web controls MYE gene web, with genes encoding the gap junction proteins (connexins, Cx) Cx29, Cx32 and Cx47 playing central roles. The novel Prominent Gene Analysis (that refines iteratively the functional webs to optimize the interconnectivity and expression stability of the associated genes) was used to select and rank the most relevant MYE and ICS genes and build the corresponding gene webs. Determine the modifications of the myelination transcriptome induced in Oli- neu control cells by differentiating treatment and proximity of cortical astrocytes. Four culture dishes of each of control, differentiated and in the astrocyte proximity Oli-neu cells were profiled using Duke mouse 30K and 36k oligonucleotide arrays in the "multiple yellow" hybrization design.

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Reducing astrocyte calcium signaling in vivo alters striatal microcircuits and causes repetitive behavior II

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