Optogenetic Countering of Glial Acidosis Suppresses Glial Glutamate Release and Ischemic Brain Damage

Beppu, Kiichiro; Sasaki, Takuya; Tanaka, Kenji F.; Yamanaka, Akihiro; Fukazawa, Yugo; Shigemoto, Ryuichi; Matsui, Kosuke

doi:10.1016/j.neuron.2013.11.011

Cited by 174 publications

(194 citation statements)

References 41 publications

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“…6C) and outward currents were detected in V-clamp (Fig. S8) similarly to a recent study that expressed ArchT in astrocytes in the cerebellum (58).…”

Section: Glun1 Expressed In Astrocytes Promotes the Differences In Ppsupporting

confidence: 86%

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Letellier

Park

Chater

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

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Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-D-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca 2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca 2+ channels. Intracellular infusion of NMDARs or Ca 2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocytedependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites.synapse heterogeneity | synaptic strength | astrocyte | hippocampal neuron | heterosynaptic plasticity A n enduring challenge in neurobiology is to understand how neurons set the strengths of their numerous synapses to efficiently process and store different information while maintaining network homeostasis. Electrophysiology and imaging approaches have revealed that synapses display a high degree of functional heterogeneity, even for those sharing the same axon or dendrite (1-3). The observation that synaptic strengths are heterogeneous, in turn, suggests that synapses can operate independently from one another. Accordingly, many studies have demonstrated the input-specificity of Hebbian and also of homeostatic forms of synaptic plasticity, where synaptic changes are restricted to inputs whose activity is altered (4-6). Nevertheless, such a synapse-autonomous behavior could potentially compromise the global network homeostasis by biasing the overall activity toward excitation or depression, and to overcome this issue, it has been proposed that distinct inputs cooperate by coordinating their relative strengths through heterosynaptic interactions (7-9). In support of the idea that synapses behave as interdependent rather than isolated functional units, the restriction of synaptic strength changes to active inputs has been demonstrated to break down at times, with the induction of synaptic plasticity in the stimulated input accompanying either synaptic depression or potentiation of the nonstimulated inputs (10-13). In a highly studied plasticity paradigm of long-term potentiation (LTP) at hippocampal Schaffer collateral-CA1 synapses, tetanic stimulation that induces LTP is often accompanied by presynaptic long-term depression (LTD) of nonstimulated Schaffer collat...

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“…6C) and outward currents were detected in V-clamp (Fig. S8) similarly to a recent study that expressed ArchT in astrocytes in the cerebellum (58).…”

Section: Glun1 Expressed In Astrocytes Promotes the Differences In Ppsupporting

confidence: 86%

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Letellier

Park

Chater

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

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“…Heterocellular electrical coupling in the CNS may be a crucial player in the development of epilepsy (34) and ischemic brain damage (35). Additional insight into underlying mechanisms will benefit from optogenetic targeting of reporter proteins to various cell subpopulations in excitable organs.…”

Section: Discussionmentioning

confidence: 99%

Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics

Quinn

Camelliti

Rog-Zielinska

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

193

177

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Electrophysiological studies of excitable organs usually focus on action potential (AP)-generating cells, whereas nonexcitable cells are generally considered as barriers to electrical conduction. Whether nonexcitable cells may modulate excitable cell function or even contribute to AP conduction via direct electrotonic coupling to AP-generating cells is unresolved in the heart: such coupling is present in vitro, but conclusive evidence in situ is lacking. We used genetically encoded voltage-sensitive fluorescent protein 2.3 (VSFP2.3) to monitor transmembrane potential in either myocytes or nonmyocytes of murine hearts. We confirm that VSFP2.3 allows measurement of cell type-specific electrical activity. We show that VSFP2.3, expressed solely in nonmyocytes, can report cardiomyocyte AP-like signals at the border of healed cryoinjuries. Using EM-based tomographic reconstruction, we further discovered tunneling nanotube connections between myocytes and nonmyocytes in cardiac scar border tissue. Our results provide direct electrophysiological evidence of heterocellular electrotonic coupling in native myocardium and identify tunneling nanotubes as a possible substrate for electrical cell coupling that may be in addition to previously discovered connexins at sites of myocyte-nonmyocyte contact in the heart. These findings call for reevaluation of cardiac nonmyocyte roles in electrical connectivity of the heterocellular heart.

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“…Nevertheless, transgenic studies also reveal the potential for certain aspects of astrogliosis to exacerbate inflammation after traumatic injury or autoimmune challenge (Brambilla et al 2005(Brambilla et al , 2009Spence et al 2011Spence et al , 2013. Other studies show that controlling astrocyte pH can reduce glutamate excitotoxicity during ischemia (Beppu et al 2014;Sloan and Barres 2014). Large-scale gene expression evaluations show that inflammatory mediators can drive astrocyte transcriptome profiles toward proinflammatory and potentially cytotoxic phenotypes (Hamby et al 2012;Zamanian et al 2012) that may be beneficial in microbial infection but may be detrimental if triggered during sterile (uninfected) tissue responses to trauma, stroke, degenerative disease, or autoimmune attack, as discussed below (Sofroniew 2013).…”

Section: Beneficial Functions and Maladaptive Effects Of Astrogliosismentioning

confidence: 99%

Astrogliosis

Sofroniew¹

2014

Cold Spring Harb Perspect Biol

568

513

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Optogenetic Countering of Glial Acidosis Suppresses Glial Glutamate Release and Ischemic Brain Damage

Cited by 174 publications

References 41 publications

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics

Astrogliosis

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