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prof. Stas Glazewski

Keele University, England

Impact of Astrocytes on Neuronal Activity

In recent years, it has emerged whereby astrocytes play a far greater role in brain function than was previously envisaged. This includes their participation in regulation of brain’s 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, neurotransmitters uptake and even sleep. Astrocytes are also increasingly acknowledged as being active partners with neurons in synaptic communication. They sense the same synaptic inputs as neurons and respond with intracellular Ca2+ elevations, which in turn may elicit the release of gliotransmitters such as ATP, D-serine, GABA and glutamate. Release of gliotransmitters has been implicated in various 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 a mouse. The neocortex exhibits two general forms of neuronal plasticity. One form, termed Hebbian plasticity concerns changes in synaptic transmission at individual inputs to neurones and their connectivity and is thought to be engaged in coding of external stimuli. The second, called homeostatic plasticity serves to maintain a restricted dynamic range of neuronal activity. Here we demonstrate that: (1) optogenetic and chemogenetic stimulation of astrocytes via IP3 (inositol triphosphate) pathway potentiates neuronal firing in vitro and in vivo; (2) IP3R2 deficiency (type 2 receptor for IP3 that is present in astrocytes, but not in neurones) results in diminished DHPG ((S)-3,5-Dihydroxyphenylglycine, group 1 metabotropic glutamate receptor specific agonist)-evoked astrocytic, but not neuronal [Ca2+] in vitro, with unchanged spontaneous and evoked neuronal firing in vivo; (3) IP3R2 knockout exhibits the impairment of experience-dependent Hebbian depression and homeostatic up-regulation and finally (4) LTD-inducing protocol evokes LTP in slices deficient in IP3R2 and after filling of astrocytes with Ca2+ chelator BAPTA ((1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid). These results demonstrate that astrocytes regulate: neuronal firing, Hebbian depression and homeostatic up-regulation in the barrel cortex.