title: Enhanced astroglial Ca2+ signaling increases excitatory synaptic strength in the epileptic brain.
abstract: The fine-tuning of synaptic transmission by astrocyte signaling is crucial to CNS physiology. However, how exactly astroglial excitability and gliotransmission are affected in several neuropathologies, including epilepsy, remains unclear. Here, using a chronic model of temporal lobe epilepsy (TLE) in rats, we found that astrocytes from astrogliotic hippocampal slices displayed an augmented incidence of TTX-insensitive spontaneous slow Ca(2+) transients (STs), suggesting a hyperexcitable pattern of astroglial activity. As a consequence, elevated glutamate-mediated gliotransmission, observed as increased slow inward current (SICs) frequency, up-regulates the probability of neurotransmitter release in CA3-CA1 synapses. Selective blockade of spontaneous astroglial Ca(2+) elevations as well as the inhibition of purinergic P2Y1 or mGluR5 receptors relieves the abnormal enhancement of synaptic strength. Moreover, mGluR5 blockade eliminates any synaptic effects induced by P2Y1R inhibition alone, suggesting that the Pr modulation via mGluR occurs downstream of P2Y1R-mediated Ca(2+)-dependent glutamate release from astrocyte. Our findings show that elevated Ca(2+)-dependent glutamate gliotransmission from hyperexcitable astrocytes up-regulates excitatory neurotransmission in epileptic hippocampus, suggesting that gliotransmission should be considered as a novel functional key in a broad spectrum of neuropathological conditions.
authors.affiliation: Centro De Neurobiología Y Plasticidad Cerebral CNPC, Instituto De Fisiología, Facultad De Ciencias, Universidad De Valparaíso, Chile.
authors.forename: Carla
authors.initials: C
authors.lastname: Álvarez-Ferradas
authors.affiliation: Centro De Neurobiología Y Plasticidad Cerebral CNPC, Instituto De Fisiología, Facultad De Ciencias, Universidad De Valparaíso, Chile.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Morales
authors.affiliation: Centro De Neurobiología Y Plasticidad Cerebral CNPC, Instituto De Fisiología, Facultad De Ciencias, Universidad De Valparaíso, Chile.
authors.forename: Mario
authors.initials: M
authors.lastname: Wellmann
authors.affiliation: Departamento De Biología Celular, Centro De Microscopía Avanzada CMA BIOBIO, Facultad De Ciencias Biológicas, Universidad De Concepción, Concepción, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: Nualart
authors.affiliation: Centro De Neurobiología Y Plasticidad Cerebral CNPC, Instituto De Fisiología, Facultad De Ciencias, Universidad De Valparaíso, Chile.
authors.forename: Manuel
authors.initials: M
authors.lastname: Roncagliolo
authors.affiliation: Centro De Neurobiología Y Plasticidad Cerebral CNPC, Instituto De Fisiología, Facultad De Ciencias, Universidad De Valparaíso, Chile.
authors.forename: Marco
authors.initials: M
authors.lastname: Fuenzalida
authors.affiliation: Centro De Neurobiología Y Plasticidad Cerebral CNPC, Instituto De Fisiología, Facultad De Ciencias, Universidad De Valparaíso, Chile.
authors.forename: Christian
authors.initials: C
authors.lastname: Bonansco
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D007696:Kindling, Neurologic; D008297:Male; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D002413:Cations, Divalent; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D058472:Receptors, Purinergic P2Y1; D002118:Calcium
keywords: astrocyte; epilepsy; gliotransmission; hippocampus; kindling; neurotransmission