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Neuronal activity determines distinct gliotransmitter release from a single astrocyte.

ABSTRACT: Accumulating evidence indicates that astrocytes are actively involved in brain function by regulating synaptic activity and plasticity. Different gliotransmitters, such as glutamate, ATP, GABA or D-serine, released form astrocytes have been shown to induce different forms of synaptic regulation. However, whether a single astrocyte may release different gliotransmitters is unknown. Here we show that mouse hippocampal astrocytes activated by endogenous (neuron-released endocannabinoids or GABA) or exogenous (single astrocyte Ca2+ uncaging) stimuli modulate putative single CA3-CA1 hippocampal synapses. The astrocyte-mediated synaptic modulation was biphasic and consisted of an initial glutamate-mediated potentiation followed by a purinergic-mediated depression of neurotransmitter release. The temporal dynamic properties of this biphasic synaptic regulation depended on the firing frequency and duration of the neuronal activity that stimulated astrocytes. Present results indicate that single astrocytes can decode neuronal activity and, in response, release distinct gliotransmitters to differentially regulate neurotransmission at putative single synapses.

SUBMITTER: Covelo A

PROVIDER: S-EPMC5790377 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Neuronal activity determines distinct gliotransmitter release from a single astrocyte.

Covelo Ana A Covelo Ana A Araque Alfonso A

eLife 20180130

Accumulating evidence indicates that astrocytes are actively involved in brain function by regulating synaptic activity and plasticity. Different gliotransmitters, such as glutamate, ATP, GABA or D-serine, released form astrocytes have been shown to induce different forms of synaptic regulation. However, whether a single astrocyte may release different gliotransmitters is unknown. Here we show that mouse hippocampal astrocytes activated by endogenous (neuron-released endocannabinoids or GABA) or ...[more]

PMID: 29380725

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Project description:Accumulation of amyloid-beta (Aβ) is associated with synaptic dysfunction and destabilization of astrocytic calcium homeostasis. A growing body of evidence support astrocytes as active modulators of synaptic transmission via calcium-mediated gliotransmission. However, the details of mechanisms linking Aβ signaling, astrocytic calcium dynamics, and gliotransmission are not known. We developed a biophysical model that describes calcium signaling and the ensuing gliotransmitter release from a single astrocytic process when stimulated by glutamate release from hippocampal neurons. The model accurately captures the temporal dynamics of microdomain calcium signaling and glutamate release via both kiss-and-run and full-fusion exocytosis. We investigate the roles of two crucial calcium regulating machineries affected by Aβ: plasma-membrane calcium pumps (PMCA) and metabotropic glutamate receptors (mGluRs). When we implemented these Aβ-affected molecular changes in our astrocyte model, it led to an increase in the rate and synchrony of calcium events. Our model also reproduces several previous findings of Aβ associated aberrant calcium activity, such as increased intracellular calcium level and increased spontaneous calcium activity, and synchronous calcium events. The study establishes a causal link between previous observations of hyperactive astrocytes in Alzheimer's disease (AD) and Aβ-induced modifications in mGluR and PMCA functions. Analogous to neurotransmitter release, gliotransmitter exocytosis closely tracks calcium changes in astrocyte processes, thereby guaranteeing tight control of synaptic signaling by astrocytes. However, the downstream effects of AD-related calcium changes in astrocytes on gliotransmitter release are not known. Our results show that enhanced rate of exocytosis resulting from modified calcium signaling in astrocytes leads to a rapid depletion of docked vesicles that disrupts the crucial temporal correspondence between a calcium event and vesicular release. We propose that the loss of temporal correspondence between calcium events and gliotransmission in astrocytes pathologically alters astrocytic modulation of synaptic transmission in the presence of Aβ accumulation.

Project description:Recent studies using the genetic partial epilepsy model have demonstrated that hyperfunction of astroglial hemichannels contributes to pathomechanism of epileptic seizure. Therefore, to explore the novel anticonvulsive mechanisms, the present study determined the effects of voltage-dependent Na+ channel (VDSC)-inhibiting anticonvulsants, carbamazepine (CBZ), lacosamide (LCM), and zonisamide (ZNS) on the astroglial release of l-glutamate and adenosine triphosphate (ATP). The effects of subchronic administration of therapeutic-relevant dose of three anticonvulsants on the release of l-glutamate and ATP in the orbitofrontal cortex (OFC) were determined using microdialysis. The concentration-dependent effects of acute and subchronic administrations of anticonvulsants on astroglial gliotransmitter release were determined using primary cultured astrocytes. The concentration-dependent effects of subchronic administrations of anticonvulsants on connexin43 (Cx43) expression in the plasma membrane of primary cultured astrocytes were determined using the Simple Western system. An increase in the levels of extracellular K+ resulted in a concentration-dependent increase in the astroglial release of l-glutamate and ATP. The depleted levels of extracellular Ca2+ alone did not affect astroglial gliotransmitter release but did accelerate K+-evoked gliotransmitter release via activation of astroglial hemichannels. Both non-selective hemichannel inhibitor carbenoxolone (CBX) and selective Cx43 inhibitor GAP19 prevented both gliotransmitter release through activated astroglial hemichannels and the hemichannel-activating process induced by elevation of the levels of extracellular K+ with depletion of the levels of extracellular Ca2+. ZNS subchronically decreased Cx43 expression and acutely/subchronically inhibited Cx43 hemichannel activity. LCM acutely inhibited hemichannel activity but did not subchronically affect Cx43 expression. Therapeutic-relevant concentration of CBZ did not affect hemichannel activity or Cx43 expression, but supratherapeutic concentration of CBZ decreased Cx43 expression and hemichannel activity. Therefore, the present study demonstrated the distinct effects of CBZ, LCM, and ZNS on gliotransmitter release via modulation of astroglial hemichannel function. The different features of the effects of three VDSC-inhibiting anticonvulsants on astroglial transmission associated with hemichannels, at least partially, possibly contributing to the formation of the properties of these three anticonvulsants, including the antiepileptic spectrum and adverse effects regarding mood and cognitive disturbance.

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Neuronal activity determines distinct gliotransmitter release from a single astrocyte.

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Neuronal activity determines distinct gliotransmitter release from a single astrocyte.

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