Molecular mechanisms of chronic stress unraveled
MedWire News: The adverse effects of chronic stress on memory are underpinned by increased turnover of glutamate receptors in the prefrontal cortex, report researchers.
The team, led by Zhen Yan (State University of New York at Buffalo, USA), previously reported that acute stress boosts working memory by enhancing glutamatergic transmission in the prefrontal cortex. But the current study demonstrates the opposite effect for chronic stress.
"Thus, glutamate receptors seem to be the neural substrate that underlies the biphasic effects of stress and glucocorticoids on synaptic plasticity and memory," the researchers write in Neuron.
They show that chronic stress (2 hours of restraint/day) significantly impaired temporal order recognition memory in rats, but that this was prevented by injecting them with antagonists of the glutamate receptors NMDAR and AMPAR.
The team used 4-week-old rats for these experiments, an age that is equivalent to adolescence in humans, when the brain is most vulnerable to the effects of stress.
Further evidence for the involvement of glutamate receptors came from measurement of NMDAR- and AMPAR-mediated synaptic currents (EPSC). Rats subjected to chronic stress had significantly reduced NMDAR-EPSC and AMPAR-EPSC, relative to control animals, but there was no evidence for changes in presynaptic function.
The effect of stress on AMPAR-EPSC changed with its duration; AMPAR synaptic transmission was significantly increased after 1 day of stress, no different from baseline after 3 days of stress, and significantly lower than baseline after 5 and 7 days of stress.
Changes in AMPAR-EPSC in response to stress occurred only in the prefrontal cortex, with no changes noted in striatal medium spiny neurons or CA1 pyramidal neurons.
The reduction in postsynaptic currents proved due to significantly increased degradation of the AMPAR and NMDAR subunits GluR1 and NR1, respectively. Again, these changes were limited to the prefrontal cortex. Other glutamate receptor subunits were unaffected, and there were no changes in presynaptic, postsynaptic, or dendritic markers.
The increased degradation of GluR1 and NR1 came about because prolonged glutamate receptor activation led to increased ubiquitination of GluR1 and NR1 (ie, "tagging" for destruction by proteasomes).
Notably, treating rats with a proteasome inhibitor prevented the stress-related reduction in postsynaptic currents and impairment of recognition memory.
"Because dysfunction in the prefrontal cortex has been implicated in stress-related mental illness, this research identifying how stress affects prefrontal cortical functions will help further unravel how and why mental illnesses occur and how to treat them," said Yan, in a press statement.
She added: "If, based on this research, we can begin to target the glutamate system in a more specific and effective way, we might be able to develop better drugs to treat serious mental illness."
By Eleanor McDermid