Astrocytes secrete ATP by exocytosis from synaptic-like vesicles, activating neuronal P2X receptors, which contribute to postsynaptic GABA receptor down-regulation, ultimately mediating the communication between astrocytes and neurons required for brain function.
The interplay between long-term potentiation and long-term depression (LTD) is thought to be involved in learning and memory formation. One form of LTD expressed in the hippocampus is initiated by the activation of the group 1 metabotropic glutamate receptors (mGluRs). Importantly, mGluRs have been shown to be critical for acquisition of new memories and for reversal learning, processes that are thought to be crucial for cognitive flexibility. Here we provide evidence that MAPK-activated protein kinases 2 and 3 (MK2/3) regulate neuronal spine morphology, synaptic transmission and plasticity. Furthermore, mGluR-LTD is impaired in the hippocampus of MK2/3 double knockout (DKO) mice, an observation that is mirrored by deficits in endocytosis of GluA1 subunits. Consistent with compromised mGluR-LTD, MK2/3 DKO mice have distinctive deficits in hippocampal-dependent spatial reversal learning. These novel findings demonstrate that the MK2/3 cascade plays a strategic role in controlling synaptic plasticity and cognition.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.