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Astrocyte IP3R2-dependent Ca(2+) signaling is not a major modulator of neuronal pathways governing behavior.

ABSTRACT: Calcium-dependent release of gliotransmitters by astrocytes is reported to play a critical role in synaptic transmission and be necessary for long-term potentiation (LTP), long-term depression (LTD) and other forms of synaptic modulation that are correlates of learning and memory. Further, physiological processes reported to be dependent on Ca(2+) fluxes in astrocytes include functional hyperemia, sleep, and regulation of breathing. The preponderance of findings indicate that most, if not all, receptor dependent Ca(2+) fluxes within astrocytes are due to release of Ca(2+) through IP3 receptor/channels in the endoplasmic reticulum. Findings from several laboratories indicate that astrocytes only express IP3 receptor type 2 (IP3R2) and that a knockout of IP3R2 obliterates the GPCR-dependent astrocytic Ca(2+) responses. Assuming that astrocytic Ca(2+) fluxes play a critical role in synaptic physiology, it would be predicted that elimination of astrocytic Ca(2+) fluxes would lead to marked changes in behavioral tests. Here, we tested this hypothesis by conducting a broad series of behavioral tests that recruited multiple brain regions, on an IP3R2 conditional knockout mouse model. We present the novel finding that behavioral processes are unaffected by lack of astrocyte IP3R-mediated Ca(2+) signals. IP3R2 cKO animals display no change in anxiety or depressive behaviors, and no alteration to motor and sensory function. Morris water maze testing, a behavioral correlate of learning and memory, was unaffected by lack of astrocyte IP3R2-mediated Ca(2+)-signaling. Therefore, in contrast to the prevailing literature, we find that neither receptor-driven astrocyte Ca(2+) fluxes nor, by extension, gliotransmission is likely to be a major modulating force on the physiological processes underlying behavior.

SUBMITTER: Petravicz J

PROVIDER: S-EPMC4228853 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Astrocyte IP3R2-dependent Ca(2+) signaling is not a major modulator of neuronal pathways governing behavior.

Petravicz Jeremy J Boyt Kristen M KM McCarthy Ken D KD

Frontiers in behavioral neuroscience 20141112

Calcium-dependent release of gliotransmitters by astrocytes is reported to play a critical role in synaptic transmission and be necessary for long-term potentiation (LTP), long-term depression (LTD) and other forms of synaptic modulation that are correlates of learning and memory. Further, physiological processes reported to be dependent on Ca(2+) fluxes in astrocytes include functional hyperemia, sleep, and regulation of breathing. The preponderance of findings indicate that most, if not all, r ...[more]

PMID: 25429263

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Project description:After ischemic stroke, various damage-associated molecules are released from the ischemic core and diffuse to the ischemic penumbra, activating microglia and promoting proinflammatory responses that may cause damage to the local tissue. Here we demonstrate using in vivo and in vitro models that, during sublethal ischemia, local neurons rapidly produce interleukin-4 (IL-4), a cytokine with potent anti-inflammatory properties. One such anti-inflammatory property includes its ability to polarize macrophages away from a proinflammatory M1 phenotype to a "healing" M2 phenotype. Using an IL-4 reporter mouse, we demonstrated that IL-4 expression was induced preferentially in neurons in the ischemic penumbra but not in the ischemic core or in brain regions that were spared from ischemia. When added to cultured microglia, IL-4 was able to induce expression of genes typifying the M2 phenotype and peroxisome proliferator activated receptor ? (PPAR?) activation. IL-4 also enhanced expression of the IL-4 receptor on microglia, facilitating a "feedforward" increase in (1) their expression of trophic factors and (2) PPAR?-dependent phagocytosis of apoptotic neurons. Parenteral administration of IL-4 resulted in augmented brain expression of M2- and PPAR?-related genes. Furthermore, IL-4 and PPAR? agonist administration improved functional recovery in a clinically relevant mouse stroke model, even if administered 24 h after the onset of ischemia. We propose that IL-4 is secreted by ischemic neurons as an endogenous defense mechanism, playing a vital role in the regulation of brain cleanup and repair after stroke. Modulation of IL-4 and its associated pathways could represent a potential target for ischemic stroke treatment.Depending on the activation signal, microglia/macrophages (M?) can behave as "healing" (M2) or "harmful" (M1). In response to ischemia, damaged/necrotic brain cells discharge factors that polarize M? to a M1-like phenotype. This polarization emerges early after stroke and persists for days to weeks, driving secondary brain injury via proinflammatory mediators and oxidative damage. Our study demonstrates that, to offset this M1-like polarization process, sublethally ischemic neurons may instead secrete a potent M2 polarizing cytokine, interleukin-4 (IL-4). In the presence of IL-4 (including when IL-4 is administered exogenously), M? become more effective in the cleanup of ischemic debris and produce trophic factors that may promote brain repair. We propose that IL-4 could represent a potential target for ischemic stroke treatment/recovery.

Dataset Information

Astrocyte IP3R2-dependent Ca(2+) signaling is not a major modulator of neuronal pathways governing behavior.

Publications

Astrocyte IP3R2-dependent Ca(2+) signaling is not a major modulator of neuronal pathways governing behavior.

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