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.

Prokineticin‐2 promotes chemotaxis and alternative A2 reactivity of astrocytes

“…Therefore, we examined whether recombinant human PK2 (rPK2) could induce functional changes in isolated primary mouse astrocytes, such as increased intracellular calcium and cell proliferation. Astrocyte calcium signaling also has an important function in regulating synaptic strength and could be used as a measure of CNS dysfunction (Álvarez-Ferradas et al 2015). Using the Fluo4-NW intracellular calcium dye, we demonstrate that rPK2 treatment induced a dose-dependent increase in intracellular calcium in primary mouse astrocytes (Figure 1D).…”

“Targeting astrocytes in CNS injury and disease: A translational research approach”

“…Conditional deletion of the glutamate receptor GLT-1 in reactive astrocytes resulted in seizures and lower body weight (Petr et al, 2015). Elevated glutamate-mediated calcium signaling in astrocytes makes them hyperexcitable, leading to enhanced excitatory neurotransmission in epileptic hippocampal slices (Álvarez-Ferradas et al, 2015). Astrocytes in hippocampal slices of human patients suffering from temporal lobe epilepsy displayed prolonged depolarization and reduced inward rectifier currents (Hinterkeuser et al, 2000), implicating K+ homeostasis as an important contributor to epilepsy.…”

Role of NMDA Receptor-Mediated Glutamatergic Signaling in Chronic and Acute Neuropathologies

“…Glutamate transporters GLT-1 and GLAST present in glial cells regulate the extracellular glutamate and limit excitotoxicity by clearing off excess glutamate [60]. Part of the loss of functionality of astrocytes is triggered by inflammatory cytokines including TNF- α , which is found at high levels in cerebrospinal fluid within 24 h of brain trauma [61].…”

“…Astrocytes control the excess of glutamate from spillover, and when their functionality is compromised, the effect of excitotoxicity is exacerbated after TBI. Astrocytes also influence and regulate neuronal excitability [62], neurotransmission [63, 64], and plasticity in glutamatergic synapses [60], but the mechanisms underlying their role in TBI have not been explored.…”