Multiplexed changes in synaptic transmission underlie stress-induced reduction of persistent firing in the parietal cortex

Abstract

Repeated exposure to stress disrupts cognitive processes, including attention and working memory. A key mechanism supporting these functions is the ability of neurons to sustain action potential firing, even after a stimulus is no longer present. How stress impacts this persistent neuronal activity is currently unknown. We found that repeated exposure to multiple concurrent stressors during adolescence (aRMS) impedes the ability of layer 5 pyramidal neurons (L5 PNs) in the posterior parietal cortex (PPC) to produce persistent firing. To determine the mechanisms underlying this effect, we complemented computational modelling with whole-cell patch clamp electrophysiology in acute brain slices from male mice. Our model predicted that altered intrinsic excitability, reduced local connectivity, diminished glutamatergic transmission, or enhanced inhibition could explain diminished persistent activity. In ex vivo experiments, we found minimal effect of aRMS on excitability and recurrent connectivity. However, stress exposure altered the properties of excitatory connections between L5 PNs, specifically affecting decay kinetics and short-term synaptic dynamics. In addition, aRMS increased inhibitory tone in the PPC, altering both GABAa and GABAb receptor-mediated responses. Incorporating the observed physiological changes into our network model, we found that no single parameter was sufficient alone to reproduce the stress-induced reduction in persistent firing. Rather, a combination of altered excitatory and inhibitory synaptic transmission was necessary to impact sustained activity. These data suggest that a multitude of converging changes in neural and circuit function underpin the effects of stress on cognitive processes. HighlightsO_LIStress exposure impairs persistent firing in the posterior parietal cortex. C_LIO_LIGABAergic inhibition is enhanced following stress. C_LIO_LIStress alters excitatory transmission between layer 5 pyramidal cells. C_LIO_LICombined changes in inhibition and excitation impact persistent firing. C_LI