Enhanced astroglial Ca2+ signaling increases excitatory synaptic strength in the epileptic brain

• Published in: Glia Vol. 63; no. 9; pp. 1507 - 1521
• Main Authors: Álvarez-Ferradas, Carla, Morales, Juan Carlos, Wellmann, Mario, Nualart, Francisco, Roncagliolo, Manuel, Fuenzalida, Marco, Bonansco, Christian
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.09.2015; Wiley Subscription Services, Inc
• Subjects: Animals; astrocyte; Astrocytes - drug effects; Astrocytes - pathology; Astrocytes - physiology; Brain - drug effects; Brain - pathology; Brain - physiopathology; Calcium - metabolism; Cations, Divalent - metabolism; Chronic Disease; Disease Models, Animal; Epilepsy; Epilepsy, Temporal Lobe - drug therapy; Epilepsy, Temporal Lobe - pathology; Epilepsy, Temporal Lobe - physiopathology; gliotransmission; hippocampus; Immunohistochemistry; kindling; Kindling, Neurologic; Male; neurotransmission; Patch-Clamp Techniques; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5 - metabolism; Receptors, Purinergic P2Y1 - metabolism; Synapses - drug effects; Synapses - pathology; Synapses - physiology; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Tissue Culture Techniques; epilepsy; neurotransmission; hippocampus; astrocyte; gliotransmission; kindling
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.22817

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 Ca2+ 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 Ca2+ 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 Ca2+‐dependent glutamate release from astrocyte. Our findings show that elevated Ca2+‐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. GLIA 2015;63:1507–1521 Main Points Epileptic hippocampus exhibits astroglial Ca2+ hyperactivity and an increased rate of glutamate gliotransmission, which upregulates the excitatory synaptic efficacy. P2Y1R and mGluR5 are involved in the abnormal astrocyte‐neuron communication.