The impact of astroglial dysfunction on excitatory synaptic transmission in neuropathological conditions: the epileptic hippocampus / Carla Álvarez Ferradas.

Doctor en Ciencias con mención en Neurociencias.

Astroglial cells are essential components of brain machinery. Indeed, astrocytes modulate synaptic transmission, neuronal excitability and plasticity in healthy brain, through the Ca2+- dependent release of neuroactive substances, process referred to as gliotransmision. Despite that altered astroglial physiology has been observed in several neuropathological conditions including epilepsy, whether the astroglial Ca2+-dependent modulation of synaptic transmission is also altered in such pathologies remains poorly understood. By using a chronic model of epilepsy, the kindling, we investigated how astroglial physiology is affected by the epileptogenesis induction, and what is the functional impact of altered astroglial physiology on neuronal transmission. Because spontaneous astroglial Ca2+-mediated glutamate gliotransmission is believed to modulate the hippocampal excitatory synaptic efficacy, spontaneous astroglial Ca2+ elevations as well as CA3-CA1 synapses electrophysiological properties were recorded from control and epileptic rats. Astrocytes from epileptic slices display slow spontaneous Ca2+ transients and higher frequency of glutamate gliotransmission -evaluated the astrocyte-dependent slow inward currents (SICs) recorded form CA1 neurons- than control slices. CA1 SC-evoked, spontaneous and miniature excitatory postsynaptic currents (eEPSC, sEPSC and mEPSC respectively) from epileptic slices showed an increased synaptic efficacy compare to control slices. The increased mEPSC frequency with no changes in mEPSC amplitude, the lowered pair-pulse facilitation index (PPF) and the increased number of successful responses evoked by minimal stimulation (meEPSC) obtained in epileptic slices suggest that the elevated excitatory synaptic efficacy was mainly mediated by an increase in the probability of neurotransmitter release (Pr). Remarkably, when astroglial Ca2+ signal were blocked by the intracellular dialysis of BAPTA, there was a strong decrease on the synaptic efficacy of CA3-CA1 synapses from epileptic slices down to control values. P2Y purinergic receptors and group I 2 glutamatergic metabotropic receptors (mGluR) antagonists also produced a decrease of the Pr. Specifically, the data suggests that P2Y1R are involved in the astroglial Ca2+-signal required for gliotransmission; and mGluR5 presynaptic receptors directly modulate neurotransmitter release. These findings showed that astroglial Ca2+-signaling is increased in the epileptic tissue strongly impacting synaptic function, which likely contribute to the pathophysiology of epilepsy.