Preserving Neuronal Plasticity During Stress
The prefrontal cortex (PFC) of the brain plays a key role in higher order mental processes such as cognition, motivation, attention, and memory. Stress can alter synaptic transmission in the PFC, and these changes may exacerbate symptoms of many psychiatric disorders. Glutamate is the primary excitatory neurotransmitter in the PFC, acting at one or more of three ionotropic glutamate receptors (AMPA, NMDA, kainate), all of which open ion channels upon ligand binding. However, transmission at glutamatergic synapses is also regulated by metabotropic glutamate receptors, which signal through G proteins. Now, Vanderbilt Basic Sciences investigators Jeff Conn and Craig Lindsley and their labs show that metabotropic glutamate receptor-3 (mGlu3) modulates glutamatergic neurotransmission in the PFC, and that this regulation is compromised following stress exposure. The investigators monitored the electrical activity of individual PFC pyramidal neurons in response to a dual mGlu2/mGlu3 agonist in the presence and absence of an mGlu3 negative allosteric modulator. These studies revealed that mGlu3 stimulation causes long term depression (LTD) of synaptic activity in the cells. More detailed electrophysiological and pharmacological studies indicated that the mGlu3-mediated LTD occurred at the post-synaptic cell, and was likely due to the internalization of AMPA receptors. Glutamatergic impulses come to the PFC from the ventral hippocampus (VH) or basolateral amygdala (BLA). To determine the source of mGlu3-mediated LTD signaling, the researchers expressed channelrhodopsin-2 (ChR2) in each of these brain regions in mice. ChR2 enabled them to use light exposure to selectively activate each region in brain slices from the mice. The results demonstrated clearly that LTD was caused by excitation of the BLA, suggesting that it might be involved in regulating emotional responses. This finding led them to explore the effects of a restraint stress on mGlu3-mediated LTD. They found that cortical slices from mice that had been exposed to stress were unable to develop LTD in response to mGlu3 activation. They also found that stressed mice performed poorly on a learned task that required PFC-mediated executive functions. However, if the mice were treated with an mGlu3 negative allosteric modulator during stress exposure, mGlu3-mediated LTD was restored as was their ability to perform the learned task. These findings suggest that stress leads to a failure of mGlu3-dependent neuronal regulation in the PFC, likely due to overstimulation of mGlu3 receptors. Protection of mGlu3 with a negative allosteric modulator during stress preserves its function and blocks the negative effects of stress on PFC-mediated cognitive functions. Thus, mGlu3 may be a target for therapy of stress-related neuropsychiatric disorders. The work is published in the journal Molecular Psychiatry [M. E. Joffe, et al. Mol. Psychiatry, (2017) published online Dec 21, DOI: 10.1038/s41380-017-0015-z].