Astrocyte-mediated activation of neuronal kainate receptors

Abstract

Exogenous kainate receptor agonists have been shown to modulate inhibitory synaptic transmission in the hippocampus, but the pathways involved in physiological activation of the receptors remain largely unknown. Accumulating evidence indicates that astrocytes can release glutamate in a Ca 2؉ -dependent manner and signal to neighboring neurons. We tested the hypothesis that astrocyte-derived glutamate activates kainate receptors on hippocampal interneurons. We report here that elevation of intracellular Ca 2؉ in astrocytes, induced by uncaging Ca 2؉ , o-nitrophenyl-EGTA, increased action potential-driven spontaneous inhibitory postsynaptic currents in nearby interneurons in rat hippocampal slices. This effect was blocked by ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)͞kainate glutamate receptor antagonists, but not by selective AMPA receptor or N-methyl-Daspartate receptor antagonists. This pharmacological profile indicates that kainate receptors were activated during Ca 2؉ elevation in astrocytes. Kainate receptors containing the GluR5 subunit seemed to mediate the observed effect because a selective GluR5-containing kainate receptor antagonist blocked the changes in sIPSCs induced by Ca 2؉ uncaging, and bath application of a selective GluR5-containing receptor agonist robustly potentiated sIPSCs. When tetrodotoxin was included to block action potentials, Ca 2؉ uncaging induced a small decrease in the frequency of miniature inhibitory postsynaptic currents, which was not affected by AMPA͞kainate receptor antagonists. Our data suggest that an astrocyte-derived, nonsynaptic source of glutamate represents a signaling pathway that can activate neuronal kainate receptors. By modulating the activity of interneurons, astrocytes may play a critical role in circuit function of hippocampus.A strocytes have traditionally been considered to function as supporting cells in the central nervous system. During the past decade, it has become increasingly clear that they actively participate in intercellular communication in the brain (1-3). They are endowed with a variety of ion channels and receptors (4-6), and they display a form of excitability by changing the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) (1-3, 7-9). Both application of neurotransmitters (1, 5, 10, 11) and electrical stimulation of neuronal pathways (12, 13) increase [Ca 2ϩ ] i in astrocytes. Thus, astrocytes sense and respond to neuronal activity by increasing [Ca 2ϩ ] i . The functional significance of this calcium signaling is still not well understood, but growing evidence suggests that it may trigger the release of glutamate and other neuroactive substances from astrocytes and thereby play a pivotal role in providing feedback to adjacent neurons and blood vessels. Such feedback can result in changes in neuronal excitability (8, 14-17), modulation of synaptic strength (18)(19)(20), an increase in neuronal [Ca 2ϩ ] i (8, 11), and a decrease in vascular tone (21).The study of astrocyte-neuron interactions is hampered by the lack of spec...

An astrocytic basis of epilepsy

“…Hippocampal slices were loaded with the Ca 2+ indicator, fluo-4/AM and viewed by twophoton laser scanning microscopy. The preferential loading of fluorescent acetoxymethyl esters indicators by astrocytes has been extensively reported [20][21][22] . Bath application of 4-AP potently initiated astrocytic Ca 2+ signaling expressed as infrequent Ca 2+ oscillations (Fig.…”

“…5a) 22 . Increases in astrocytic Ca 2+ evoked by uncaging of NP-EGTA triggered in 8 of 12 experiments a PDS, whereas UV-flash in an identical fashion of slices not loaded with NP-EGTA failed to increase astrocytic Ca 2+ concentration or to evoke PDSs (n = 15) (Fig.…”

“…Whole-cell recordings from CA1 pyramidal neurons and stratum radiatum astrocytes in hippocampal slices were performed as previously described 22 of CA1 in hippocampal slices as previously described 45 . Recording signals were filtered at 1 kHz, digitized at 5 kHz.…”

“…Whole-cell recordings from CA1 pyramidal neurons and stratum radiatum astrocytes in hippocampal slices were performed as previously described 22 . The perfusion artificial cerebrospinal fluid (ACSF) contained (in mM): 125 NaCl, 5 KCl, 1.25 NaH 2 PO 4 , 2 MgCl 2 , 2 CaCl 2 , 10 glucose and 25 NaHCO 3 , pH 7.4 when aerated with 95% O 2 , 5% CO 2 45 .…”

Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics

“…Some pathways involved in physiological activation of KA receptors are still unknown, 7 although physiological studies have identified both post-and presynaptic roles for KA receptors. This class of receptors has also been suggested to play an important role in short-and long-term synaptic plasticity.…”