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 ATP release from astrocytes remain uncertain with exocytosis being the most intriguing and debated pathway. We have demonstrated that ATP and d-serine can be released from cortical astrocytes in situ by a SNARE-complex-dependent mechanism. Exocytosis of ATP from astrocytes can activate post-synaptic P2X receptors in the adjacent neurons, causing a downregulation of synaptic and extrasynaptic GABA receptors in cortical pyramidal neurons. We showed that release of gliotransmitters is important for the NMDA receptor-dependent synaptic plasticity in the neocortex. Firstly, induction of long-term potentiation (LTP) by five episodes of theta-burst stimulation (TBS) was impaired in the neocortex of dominant-negative (dn)-SNARE mice. The LTP was rescued in the dn-SNARE mice by application of exogenous non-hydrolysable ATP analogues. Secondly, we observed that weak sub-threshold stimulation (two TBS episodes) became able to induce LTP when astrocytes were additionally activated via CB-1 receptors. This facilitation was dependent on activity of ATP receptors and was abolished in the dn-SNARE mice. Our results strongly support the physiological relevance of glial exocytosis for glia–neuron communications and brain function.
Highlights
Cannabinoid receptors are important modulators of synaptic transmission, implicated in the short- and long-term plasticity of inhibitory and excitatory synapses in many regions of the central nervous system [1]
This observation closely agrees with our previous experiments carried out in the neocortical slices where we demonstrated that TFLLR-induced purinergic mEPSCs of smaller amplitude and slower kinetics originated from the vesicular release of ATP from astrocytes [25]
long-term potentiation (LTP) induction in the dn-SNARE mice. These results strongly suggest that CB1 receptors contribute to regulation of exocytosis of gliotransmitters, in particular ATP, and this pathway is important for synaptic plasticity in the neocortex
Summary
Cannabinoid receptors are important modulators of synaptic transmission, implicated in the short- and long-term plasticity of inhibitory and excitatory synapses in many regions of the central nervous system [1]. It has been shown that CB1 receptors of hippocampal astrocytes can trigger release of glutamate, which in turn can activate post-synaptic NMDA receptors on CA1 pyramidal neurons or pre-synaptic mGuR1 receptors [9,10] The latter mechanism was reported to cause short-term facilitation of transmitter release at some population of excitatory synapses. The mechanism of eCB-dependent depression involved, presum- 2 ably, release of glutamate from astrocytes leading to activation of post-synaptic NMDA receptors and subsequent endocytosis of AMPA receptors [8]. These results contrast with the observation of eCB-mediated potentiation of synaptic transmission in hippocampus via astrocytic CB1 receptors [10]. We use a combination of techniques, including the ‘sniffer’-cell approach [25], and transgenic mice with inducible expression of the dominantnegative (dn)-SNARE domain selectively in astrocytes [24]
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