In recent years, it has emerged that astrocytes play a far greater role in brain function than previ‑ ously envisaged. This includes their participation in the regulation of brain blood flow, formation of blood-brain and CSF-brain barriers, homeostasis of interstitial fluid, removal of metabolites from the interstitial spaces, formation of astrocytic scars due to brain injury, neurotransmitter uptake, and even sleep. Astrocytes are also increasingly acknowledged as active partners with neurons in synaptic commu‑ nication. They sense the same synaptic inputs as neu‑ rons and respond with intracellular Ca2+ elevations, which in turn may elicit the release of gliotransmit‑ ters such as ATP, D-serine, GABA, and glutamate. Re‑ lease of gliotransmitters has been described in var‑ ious in vitro models of synaptic plasticity, including short- and long-term potentiation (LTP), long-term depression (LTD), and heterosynaptic depression. We have recently addressed the impact of astrocytes on neuronal activity and plasticity in the barrel cortex of mouse. The neocortex exhibits two general forms of neuronal plasticity. One form, termed Hebbian plas‑ ticity, concerns changes in synaptic transmission at individual inputs to neurons and their connectivity and is thought to be involved in the coding of exter‑ nal stimuli. The second, called homeostatic plasticity, serves to maintain a restricted dynamic range of neu‑ ronal activity. Here we demonstrate that: (1) optoge‑ netic and chemogenetic stimulation of astrocytes via the IP3 (inositol triphosphate) pathway potentiates neuronal firing in vitro and in vivo; (2) IP3R2 defi‑ ciency (type 2 receptor for IP3 that is present in astro‑ cytes, but not in neurons) results in diminished DHPG ((S)-3,5-Dihydroxyphenylglycine, a selective group 1 metabotropic glutamate receptor agonist)-evoked astrocytic, but not neuronal [Ca2+] in vitro, with un‑ changed spontaneous and evoked neuronal firing in vivo; (3) IP3R2 knockout results in impairment of ex‑ perience-dependent Hebbian depression and homeo‑ static up-regulation and finally (4) an LTD-inducing protocol evokes LTP in slices deficient in IP3R2 and in wild type slices after filling astrocytes with the Ca2+ chelator BAPTA ((1,2-bis(o-aminophenoxy)ethaneN,N,N′,N′-tetraacetic acid). These results demon‑ strate that astrocytes regulate neuronal firing, Hebbi‑ an depression, and homeostatic up-regulation in the barrel cortex.
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