Abstract
Communication between neuronal and glial cells is thought to be very important for many brain functions. Acting via release of gliotransmitters, astrocytes can modulate synaptic strength. The mechanisms underlying gliotransmission remain uncertain with exocytosis being the most intriguing and debated pathway. We demonstrate that astroglial α1-adrenoreceptors are very sensitive to noradrenaline (NA) and make a significant contribution to intracellular Ca2+-signaling in layer 2/3 neocortical astrocytes. We also show that astroglial α1-adrenoreceptors are prone to desensitization upon prolonged exposure to NA. We show that within neocortical slices, α-1adrenoreceptors can activate vesicular release of ATP and D-serine from cortical astrocytes which initiate a burst of ATP receptor-mediated currents in adjacent pyramidal neurons. These purinergic currents can be inhibited by intracellular perfusion of astrocytes with Tetanus Toxin light chain, verifying their origin via astroglial exocytosis. We show that α1 adrenoreceptor-activated release of gliotransmitters is important for the induction of synaptic plasticity in the neocortex:long-term potentiation (LTP) of neocortical excitatory synaptic potentials can be abolished by the selective α1-adrenoreceptor antagonist terazosin. We show that weak sub-threshold theta-burst stimulation (TBS) can induce LTP when astrocytes are additionally activated by 1 μM NA. This facilitation is dependent on the activation of neuronal ATP receptors and is abolished in neocortical slices from dn-SNARE mice which have impaired glial exocytosis. Importantly, facilitation of LTP by NA can be significantly reduced by perfusion of individual astrocytes with Tetanus Toxin. Our results strongly support the physiological importance of astroglial adrenergic signaling and exocytosis of gliotransmitters for modulation of synaptic transmission and plasticity.
Highlights
It is generally acknowledged that astrocytes are very important components of brain networks
We demonstrate that astroglial α1-ARs can activate exocytosis of gliotransmitters, in particular ATP, and this mechanism contributes to modulation of synaptic plasticity in neocortical neurons
We previously demonstrated that pyramidal neocortical neurons express functional P2X receptors (Pankratov et al, 2007) and these receptors can be activated by ATP released from astrocytes (Lalo et al, 2014a)
Summary
It is generally acknowledged that astrocytes are very important components of brain networks. There is an accumulating evidence that Ca2+signaling in brain astrocytes can be activated by synaptically-derived neurotransmitters (Lalo et al, 2011a, 2014a; Palygin et al, 2011; Panatier et al, 2011), by the local autocrine release of gliotransmitters such as glutamate or ATP (Araque et al, 2014) and via diffuse volume-transmitted neuromodulators such as serotonin, acetylcholine or noradrenaline (NA; Schipke et al, 2008; Ding et al, 2013; Paukert et al, 2014; Khakh and McCarthy, 2015). A number of recent studies have used NA as a tool for the activation of astrocytes and showed that NA-evoked and glia-derived ATP can modulate excitatory synapses in the hippocampus and hypothalamus (Gordon et al, 2009; Pougnet et al, 2014) These papers do not provide direct evidence for adrenoreceptor-triggered release of gliotransmitters and report opposing effects of gliaderived ATP on AMPA receptors trafficking. We use a combination of approaches including transgenic mice with inducible astroglial expression of dominant-negative SNARE domain (dn-SNARE; Pascual et al, 2005), intracellular perfusion of astrocytes with Ca2+-chelators and inhibitors of SNARE proteins
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