Synaptic plasticity – the ability of neurons to increase or decrease the strength of signal transmission in response to changes in synaptic activity – is a key process in learning, cognition, and memory. Considerable data suggest that noradrenergic neurons that project their axons to the cortex and hippocampus play a role in the development and retention of memories associated with fear or stress. They do this by promoting long-term potentiation, a form of synaptic plasticity characterized by a sustained increase in signal transmission in response to a stimulus, which is often glutamate released by excitatory neurons. Now, Basic Sciences investigators Jeff Conn and Craig Lindsley, along with their laboratories, use novel selective allosteric modulators of group II metabotropic glutamate receptors (mGlu2 and mGlu3) to show that mGlu3 in hippocampal astrocytes suppresses the development of long-term potentiation in response to noradrenergic stimulation. They show that noradrenaline released by noradrenergic neurons increases cAMP levels in both neurons and neighboring astrocytes. In neurons, the cAMP promotes development of long-term potentiation in response to a glutamate stimulus. However, in the astrocytes, glutamate also activates mGlu3, which increases cAMP levels even more. Breakdown of the excess cAMP yields high concentrations of adenosine that travels to the nearby excitatory glutamatergic nerve terminals, suppressing their release of glutamate. In the absence of glutamate, long-term potentiation does not develop, even if noradrenergic signaling occurs. These findings may have important implications for the prevention and/or treatment of post-traumatic stress disorder in which stress- or fear-related memories play a critical role. The work is published in the journal Neuropsychopharmacology [A. G. Walker, et al., (2017) Neuropsychopharmacology, published online June 30, 2017, DOI:10.1038/nnp.2017.136].
Image reproduced by permission from Macmillan Publishers Ltd, from A. G. Walker, et al., (2017) Neuropsychopharmacology, published online June 30, 2017, DOI:10.1038/nnp.2017.136]. Copyright 2017