Dataset Information

C-terminal-dependent control of EAAT2 signaling, corticostriatal synaptic glutamate clearance and spontaneous motor activity in mice with hypokinesia

ABSTRACT: Deficiency of the astrocytic excitatory amino acid transporter type 2 (EAAT2) and, consequently, inefficient glutamate clearance at corticostriatal synapses may contribute to the depression of self-initiated movements in HuntingtonÕs disease (HD). Here we report that the removal of the last 68 amino-acids in the C-terminal of EAAT2 increases the levels of native EAAT2 in striatal lysates and counteracts some of the HD-related changes in the interactor spectrum of mYFP-tagged EAAT2. Using the Q175 mouse model of HD, we explored the functional consequences of C-terminal modifications. It was found that astrocytic expression of EAAT2-S506X or -4KR alleviates the HD-related decrease in the incidence and velocity of exploratory movements. It also stimulates astrocytic glutamate uptake, increases the level of synaptic EAAT2 and improves glutamate clearance at single corticostriatal synapse. The experiments illuminate a link between the intracellular regulation of astrocytic glutamate transport in the striatum and symptoms of hypokinesia in HD mice.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Huntington Disease

SUBMITTER: Marieluise Kirchner

LAB HEAD: Philipp Mertins

PROVIDER: PXD029194 | Pride | 2022-01-26

REPOSITORIES: Pride

ACCESS DATA

Similar Datasets

Project description:The endoribonuclease, Dicer, is indispensible for generating the majority of mature microRNAs (miRNAs), which are posttranscriptional regulators of gene expression involved in a wide range of developmental and pathological processes in mammalian central nervous system. While functions of Dicer-dependent miRNA pathways in neurons and oligodendrocytes have been extensively investigated, little is known about the role of Dicer in astrocytes. Here we report the effect of Cre-loxP mediated conditional deletion of Dicer selectively from postnatal astroglia on brain development. Dicer-deficient mice exhibited normal motor development and neurological morphology prior to postnatal week 5. Thereafter mutant mice invariably developed a rapidly fulminant neurological decline characterized by ataxia, severe progressive cerebellar degeneration, seizures, uncontrollable movements and premature death by postnatal week 9-10. Integrated transcription profiling, histological and functional analyses of cerebella showed that deletion of Dicer in cerebellar astrocytes altered the transcriptome of astrocytes to be more similar to an immature or reactive-like state prior to the onset of neurological symptoms or morphological changes. As a result, critical and mature astrocytic functions including glutamate uptake and antioxidant pathways were substantially impaired, leading to massive apoptosis of cerebellar granule cells and degeneration of Purkinje cells. Collectively, our study demonstrates the critical involvement of Dicer in normal astrocyte maturation and maintenance. Our findings also reveal non-cell autonomous roles of astrocytic Dicer-dependent pathways in regulating proper neuronal functions and implicate that loss of or dysregulation of astrocytic Dicer-dependent pathways may be involved in neurodegeneration and other neurological disorders. Four replicate experiments using samples derived from biologically independent pairs of control (mGfap-Cre; Dicer +/flox) and Dicer mutant (mGfap-Cre; Dicer flox/flox) littermate mice (postnatal day 30) were performed with a dye-swap experimental design.

Dataset Information

C-terminal-dependent control of EAAT2 signaling, corticostriatal synaptic glutamate clearance and spontaneous motor activity in mice with hypokinesia

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure