Intracellular Astrocyte Calcium WavesIn SituIncrease the Frequency of Spontaneous AMPA Receptor Currents in CA1 Pyramidal Neurons

Abstract

Spontaneous neurotransmitter release and activation of group I metabotropic glutamate receptors (mGluRs) each play a role in the plasticity of neuronal synapses. Astrocytes may contribute to short-and long-term synaptic changes by signaling to neurons via these processes. Spontaneous whole-cell AMPA receptor (AMPAR) currents were recorded in CA1 pyramidal cells in situ while evoking Ca 2ϩ increases in the adjacent stratum radiatum astrocytes by uncaging IP 3 . Whole-cell patch clamp was used to deliver caged IP 3 and the Ca 2ϩ indicator dye Oregon green BAPTA-1 to astrocytes. Neurons were patch-clamped and filled with Alexa 568 hydrazide dye to visualize their morphological relationship to the astrocyte. On uncaging of IP 3 , astrocyte Ca 2ϩ responses reliably propagated as a wave into the very fine distal processes, synchronizing Ca 2ϩ activity within astrocyte microdomains. The intracellular astrocyte Ca 2ϩ wave coincided with a significant increase in the frequency of AMPA spontaneous EPSCs, but with no change in their kinetics. AMPAR current amplitudes were increased as well, but not significantly ( p ϭ 0.06). The increased frequency of AMPAR currents was sensitive to the group I mGluR antagonists LY367385 and 2-methyl-6-(phenylethynyl)-pyridine, suggesting that (1) astrocytes released glutamate in response to IP 3 uncaging, and (2) glutamate released by astrocytes activated group I mGluRs to facilitate the release of glutamate from excitatory neuronal presynaptic boutons. These results extend previous studies, which have shown astrocyte modulation of neuronal activity in vitro and suggest that astrocyte-to-neuron signaling in intact tissue may contribute to synaptic plasticity.

Loss of IP3Receptor-Dependent Ca2+Increases in Hippocampal Astrocytes Does Not Affect Baseline CA1 Pyramidal Neuron Synaptic Activity

“…Additionally, astrocyte Ca 2ϩ increases have been associated with neuronal Ca 2ϩ increases mediated by iGluRs (Hassinger et al, 1995;Pasti et al, 2001;Fellin et al, 2004). A mathematical model incorporating data from numerous studies, including our own (Fiacco and McCarthy, 2004), on the role of astrocytes at the tripartite synapse predicts that astrocytes enhance synaptic release (Nadkarni and Jung, 2007). This is reflected by an increase in spontaneous postsynaptic events during and immediately after astrocyte Ca 2ϩ elevations that trigger astrocytic release of glutamate compared with synapses lacking an associated astrocyte (Nadkarni and Jung, 2007).…”

“…For AMPAR sEPSC recordings, CA1 pyramidal neurons were patch clamped using pipettes (4.0 -6.0 M⍀ resistance), and a gap-free recording was performed for 10 min in ACSF as described previously (Fiacco and McCarthy, 2004). For NMDAR sEPSCs, neurons were voltage clamped at Ϫ70 mV and superfused with ACSF containing 5 M Mg 2ϩ and 10 M CNQX to block AMPA responses.…”

“…Lack of spontaneous Ca 2؉ oscillations in astrocytes does not affect CA1 pyramidal neuron sEPSCs It has been reported that spontaneous and evoked astrocyte Ca 2ϩ elevations lead to gliotransmitter release, which modulates basal neuronal excitatory and inhibitory synaptic activity via the activation of neuronal mGluRs and iGluRs (Hassinger et al, 1995;Araque et al, 1998b;Kang et al, 1998;Parri et al, 2001;Fiacco and McCarthy, 2004;Liu et al, 2004a,b). The effect of blocking astrocyte Ca 2ϩ elevations and therefore Ca 2ϩ -dependent gliotransmitter release on basal neuronal excitatory activity has not been addressed thoroughly.…”

Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

“…Ca 2+ signals can trigger the release of gliotransmitters (glutamate, D-serine, ATP), which in turn regulate synaptic transmission [2]. Through these mechanisms, astrocytes have been proposed to play a critical role in modulating synaptic transmission [9,10], plasticity properties [11][12][13], and longterm potentiation (LTP) [14], consistent with evidence suggesting that astrocytic Ca 2+ transients can occur in spatially restricted areas [15,16]. However, other studies have also proposed different mechanisms to account for a contribution of astrocytes to plasticity and memory [17,18].…”

Neurotrophin signaling among neurons and glia during formation of tripartite synapses

“…PKC activation, in turn, promotes the maturation of excitatory presynaptic terminals, but has no effect on postsynaptic AMPA receptor cluster number and localization (Hama et al, 2004). As synapses mature, astrocytes continue to modulate synaptic function by potentiating and suppressing activity at presynaptic glutamatergic terminals via the release of glutamate and ATP, respectively (Zhang et al, 2003;Fiacco and McCarthy, 2004). Ephrin-Eph signaling between neurons and glial cells has also been suggested to modulate postsynaptic spine morphology.…”