Loss of IP3 Receptor-Dependent Ca2+ Increases in Hippocampal Astrocytes Does Not Affect Baseline CA1 Pyramidal Neuron Synaptic Activity

Astrocytes in the hippocampus release calcium (Ca2+) from intracellular stores intrinsically and in response to activation of Gq-linked G-protein coupled receptors (GPCRs) through the binding of inositol 1,4,5-trisphosphate (IP3) to its receptor (IP3R). Astrocyte Ca2+ has been deemed necessary and sufficient to trigger the release of gliotransmitters, such as ATP and glutamate, from astrocytes to modulate neuronal activity. Several lines of evidence suggest that IP3R Type 2 (IP3R2) is the primary IP3R expressed by astrocytes. In order to determine if IP3R2 is the primary functional IP3R responsible for astrocytic Ca2+ increases, we conducted experiments using an IP3R2 knockout mouse model (IP3R2 KO). We show for the first time that lack of IP3R2 blocks both spontaneous and Gq-linked GPCR mediated increases in astrocyte Ca2+. Furthermore, neuronal Gq-linked GPCR Ca2+ increases remain intact, suggesting that IP3R2 does not play a major functional role in neuronal calcium store release or may not be expressed in neurons. Additionally, we show that lack of IP3R2 in the hippocampus does not affect baseline excitatory neuronal synaptic activity as measured by spontaneous EPSC (sEPSC) recordings from CA1 pyramidal neurons. Whole cell recordings of the tonic NMDA receptor (NMDA-R) mediated current indicates that ambient glutamate levels are also unaffected in the IP3R2 KO. These data show that IP3R2 is the key functional IP3R driving Gq-linked GPCR mediated Ca2+ increases in hippocampal astrocytes and that removal of astrocyte Ca2+ increases does not significantly affect excitatory neuronal synaptic activity or ambient glutamate levels

What Is the Role of Astrocyte Calcium in Neurophysiology?

Astrocytes comprise approximately half of the volume of the adult mammalian brain and are the primary neuronal structural and trophic supportive elements. Astrocytes are organized into distinct nonoverlapping domains and extend elaborate and dense fine processes that interact intimately with synapses and cerebrovasculature. The recognition in the mid 1990s that astrocytes undergo elevations in intracellular calcium concentration following activation of G protein-coupled receptors by synaptically released neurotransmitters demonstrated not only that astrocytes display a form of excitability but also that astrocytes may be active participants in brain information processing. The roles that astrocytic calcium elevations play in neurophysiology and especially in modulation of neuronal activity have been intensely researched in recent years. This review will summarize the current understanding of the function of astrocytic calcium signaling in neurophysiological processes and discuss areas where the role of astrocytes remains controversial and will therefore benefit from further study

Nucleus basalis-enabled stimulus-specific plasticity in the visual cortex is mediated by astrocytes

Although cholinergic innervation of the cortex by the nucleus basalis (NB) is known to modulate cortical neuronal responses and instruct cortical plasticity, little is known about the underlying cellular mechanisms. Using cell-attached recordings in vivo, we demonstrate that electrical stimulation of the NB, paired with visual stimulation, can induce significant potentiation of visual responses in excitatory neurons of the primary visual cortex in mice. We further show with in vivo two-photon calcium imaging, ex vivo calcium imaging, and whole-cell recordings that this pairing-induced potentiation is mediated by direct cholinergic activation of primary visual cortex astrocytes via muscarinic AChRs. The potentiation is absent in conditional inositol 1,4,5 trisphosphate receptor type 2 KO mice, which lack astrocyte calcium activation, and is stimulus-specific, because pairing NB stimulation with a specific visual orientation reveals a highly selective potentiation of responses to the paired orientation compared with unpaired orientations. Collectively, these findings reveal a unique and surprising role for astrocytes in NB-induced stimulus-specific plasticity in the cerebral cortex.Singapore. Agency for Science, Technology and Research ((A*STAR) Fellowship)National Science Foundation (U.S.) (R01EY018648)National Science Foundation (U.S.) (R01EY007023)Simons Foundation (grant)European Commission. Community Research and Development Information Service (Marie Curie Fellowships

What Is the Role of Astrocyte Calcium in Neurophysiology?

Astrocytes comprise approximately half of the volume of the adult mammalian brain and are the primary neuronal structural and trophic supportive elements. Astrocytes are organized into distinct nonoverlapping domains and extend elaborate and dense fine processes that interact intimately with synapses and cerebrovasculature. The recognition in the mid 1990s that astrocytes undergo elevations in intracellular calcium concentration following activation of G protein-coupled receptors by synaptically released neurotransmitters demonstrated not only that astrocytes display a form of excitability but also that astrocytes may be active participants in brain information processing. The roles that astrocytic calcium elevations play in neurophysiology and especially in modulation of neuronal activity have been intensely researched in recent years. This review will summarize the current understanding of the function of astrocytic calcium signaling in neurophysiological processes and discuss areas where the role of astrocytes remains controversial and will therefore benefit from further study

Ca2+ signaling in astrocytes from Ip3r2−/− mice in brain slices and during startle responses in vivo

Intracellular Ca(2+) signaling is considered important for multiple astrocyte functions in neural circuits. However, mice devoid of inositol triphosphate type 2 receptors (IP3R2) reportedly lack all astrocyte Ca(2+) signaling, but display no neuronal or neurovascular deficits, implying that astrocyte Ca(2+) fluctuations play no role(s) in these functions. An assumption has been that loss of somatic Ca(2+) fluctuations also reflects similar loss within astrocyte processes. Here, we tested this assumption and found diverse types of Ca(2+) fluctuations within astrocytes, with most occurring within processes rather than in somata. These fluctuations were preserved in IP3R2(−)(/)(−) mice in brain slices and in vivo, occurred in endfeet, were increased by G-protein coupled receptor activation and by startle-induced neuromodulatory responses. Our data reveal novel Ca(2+) fluctuations within astrocytes and highlight limitations of studies that used IP3R2(−)(/)(−) mice to evaluate astrocyte contributions to neural circuit function and mouse behavior