Decoupling astrocytes in adult mice impairs synaptic plasticity and spatial learning

Hösli, Ladina; Binini, Noemi; Ferrari, Kim David; Thieren, Laetitia; Looser, Zoe J.; Zuend, Marc; Zanker, Henri S.; Berry, Stewart; Holub, Martin; Möbius, Wiebke; Ruhwedel, Torben; Nave, Klaus‐Armin; Giaume, Christian; Weber, Bruno; Saab, Aiman S.

doi:10.1016/j.celrep.2022.110484

Cited by 57 publications

(60 citation statements)

References 122 publications

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“…Next, we detected inflammatory cells infiltrating the hippocampus in the two groups and found that compared with those in the sham-operated group, there were an increase in the hippocampal glial cells and the soma of Iba1 + cells in the HO group ( P < 0.01, Figure 5A ). Synaptic plasticity in the hippocampus is required for cognition ( Fang et al, 2022 ; Hösli et al, 2022 ); therefore, we evaluated the co-expression of the microglial and synaptic-related proteins, the presynaptic and postsynaptic markers synaptophysin (SYN) and postsynaptic density protein 95 (PSD95). The results showed increased SYN-immunoreactive and PSD95-immunoreactive materials inside the microglial, suggesting there was more engulfment of synaptic components in HO rats ( P < 0.05, Figures 5B,C ).…”

Section: Resultsmentioning

confidence: 99%

Microglial infiltration mediates cognitive dysfunction in rat models of hypothalamic obesity via a hypothalamic-hippocampal circuit involving the lateral hypothalamic area

Wei

Wang

Zhou

et al. 2022

Front. Cell. Neurosci.

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This study aimed to explore the mechanism underlying cognitive dysfunction mediated by the lateral hypothalamic area (LHA) in a hypothalamic-hippocampal circuit in rats with lesion-induced hypothalamic obesity (HO). The HO model was established by electrically lesioning the hypothalamic nuclei. The open field (OP) test, Morris water maze (MWM), novel object recognition (NOR), and novel object location memory (NLM) tests were used to evaluate changes in cognition due to alterations in the hypothalamic-hippocampal circuit. Western blotting, immunohistochemical staining, and cholera toxin subunit B conjugated with Alexa Fluor 488 (CTB488) reverse tracer technology were used to determine synaptophysin (SYN), postsynaptic density protein 95 (PSD95), ionized calcium binding adaptor molecule 1 (Iba1), neuronal nuclear protein (NeuN), and Caspase3 expression levels and the hypothalamic-hippocampal circuit. In HO rats, severe obesity was associated with cognitive dysfunction after the lesion of the hypothalamus. Furthermore, neuronal apoptosis and activated microglia in the downstream of the lesion area (the LHA) induced microglial infiltration into the intact hippocampus via the LHA-hippocampal circuit, and the synapses engulfment in the hippocampus may be the underlying mechanism by which the remodeled microglial mediates memory impairments in HO rats. The HO rats exhibited microglial infiltration and synapse loss into the hippocampus from the lesioned LHA via the hypothalamic-hippocampal circuit. The underlying mechanisms of memory function may be related to the circuit.

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Section: Resultsmentioning

confidence: 99%

Microglial infiltration mediates cognitive dysfunction in rat models of hypothalamic obesity via a hypothalamic-hippocampal circuit involving the lateral hypothalamic area

Wei

Wang

Zhou

et al. 2022

Front. Cell. Neurosci.

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“…Moreover, our analysis showed that neurons were identified by a signature of genes mainly clustered in biological processes related to neurogenesis. Although it is well known that CX43 protein itself regulates key signalling pathways during development and neurogenesis [ 73 ], its role in modulating synaptic plasticity and compensatory processes in neurodegenerative disease is not fully elucidated [ 74 , 75 , 76 ]. Data herein described report four main neuronal biological processes that negatively correlate with GJA1 levels, namely axon development, dendritic development, synaptic transmission genes, and synaptic vesicle cycle.…”

Section: Discussionmentioning

confidence: 99%

GJA1/CX43 High Expression Levels in the Cervical Spinal Cord of ALS Patients Correlate to Microglia-Mediated Neuroinflammatory Profile

et al. 2022

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motoneurons (MNs) with a fatal outcome. The typical degeneration of cortico-spinal, spinal, and bulbar MNs, observed in post-mortem biopsies, is associated with the activation of neuroimmune cells. GJA1, a member of the connexins (Cxs) gene family, encodes for connexin 43 (Cx43), a core gap junctions (GJs)- and hemichannels (HCs)-forming protein, involved in cell death, proliferation, and differentiation. Recently, Cx43 expression was found to play a role in ALS pathogenesis. Here, we used microarray and RNA-seq datasets from the NCBI of the spinal cord of control (NDC) and ALS patients, which were stratified according to the GJA1 gene expression. Genes that positively or negatively correlated to GJA1 expression were used to perform a genomic deconvolution analysis (GDA) using neuroimmune signatures. Expression analysis revealed a significantly higher GJA1 expression in the MNs of ALS patients as compared to NDC. Gene deconvolution analysis revealed that positively correlated genes were associated with microglia activation, whereas negatively correlated genes were associated with neuronal activation profiles. Moreover, gene ontology analysis, performed on genes characterizing either microglia or neuronal signature, indicated immune activation or neurogenesis as main biological processes. Finally, using a synthetic analysis of drugs able to revert the GJA1 transcriptomic signatures, we found a specific drug profile for ALS patients with high GJA1 expression levels, composed of amlodipine, sertraline, and prednisolone. In conclusion, our exploratory study suggests GJA1 as a new neuro-immunological gene correlated to microglial cellular profile in the spinal cord of ALS patients. Further studies are warranted to confirm these results and to evaluate the therapeutic potential of drugs able to revert typical GJA1/CX43 signature in ALS patients

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“…Modulation of neuronal plasticity is a plausible candidate for such a process, since it acts on behavioral timescales 57 and takes place upon salient events 58 . Such modulation has been studied for hippocampal and other astrocytes both in vitro [59][60][61] and more recently also in vivo [62][63][64][65][66] . It remains open what output signals may be triggered by somatic activation of astrocytes, potentially instantiating feedback modulation of the surrounding neuronal processes.…”

Section: A Role For Astrocytes To Slowly Process Past Eventsmentioning

confidence: 99%

Centripetal integration of past events by hippocampal astrocytes and its regulation by the locus coeruleus

Rupprecht

Lewis

Helmchen

2022

Preprint

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An essential feature of neurons is their ability to centrally integrate information from their dendrites. The activity of astrocytes, on the other hand, has been described to be mostly uncoordinated across the cellular compartments and therefore without central integration. Here, we describe conditional centripetal integration, a principle how astrocytes integrate calcium signals from their distal processes. We performed calcium imaging of hippocampal astrocytes and neurons in head-fixed mice, together with monitoring of body movements and pupil diameter. Global astrocytic activity was well explained by the concurrent pupil diameter as a proxy for arousal, but equally well as leaky integration of past neuronal and behavioral events on a timescale of seconds. This integration of past events occurred in a centripetal pattern in individual astrocytes, starting in distal processes followed by a slow propagation towards the soma. Centripetal propagation was facilitated by high levels of arousal but impeded when pre-event calcium levels were high. Together, our results establish astrocytes as computational units of the brain that slowly and conditionally integrate information about the past.

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Decoupling astrocytes in adult mice impairs synaptic plasticity and spatial learning

Cited by 57 publications

References 122 publications

Microglial infiltration mediates cognitive dysfunction in rat models of hypothalamic obesity via a hypothalamic-hippocampal circuit involving the lateral hypothalamic area

Microglial infiltration mediates cognitive dysfunction in rat models of hypothalamic obesity via a hypothalamic-hippocampal circuit involving the lateral hypothalamic area

GJA1/CX43 High Expression Levels in the Cervical Spinal Cord of ALS Patients Correlate to Microglia-Mediated Neuroinflammatory Profile

Centripetal integration of past events by hippocampal astrocytes and its regulation by the locus coeruleus

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