Molecular and Epigenetic Mechanisms for the Complex Effects of Stress on Synaptic Physiology and Cognitive Functions

Abstract

Evidence over the past decades has found that stress, particularly through the corticosterone stress hormones, produces complex changes in glutamatergic signaling in prefrontal cortex, which leads to the alteration of cognitive processes medicated by this brain region. Interestingly, the effects of stress on glutamatergic transmission appear to be "U-shaped," depending upon the duration and severity of the stressor. These biphasic effects of acute vs chronic stress represent the adaptive vs maladaptive responses to stressful stimuli. Animal studies suggest that the stress-induced modulation of excitatory synaptic transmission involves changes in presynaptic glutamate release, postsynaptic glutamate receptor membrane trafficking and degradation, spine structure and cytoskeleton network, and epigenetic control of gene expression. This review will discuss current findings on the key molecules involved in the stress-induced regulation of prefrontal cortex synaptic physiology and prefrontal cortex-mediated functions. Understanding the molecular and epigenetic mechanisms that underlie the complex effects of stress will help to develop novel strategies to cope with stress-related mental disorders.

Keywords: AMPA receptor; E3 ligase; NMDA receptor; cognition; corticosterone stress hormones; emotion; glucocorticoid receptor; glutamatergic transmission; histone deacetylase; prefrontal cortex; protein ubiquitination; stress; stress-related mental disorders; trafficking.

Figure 1.

A diagram illustrating the complex effects of stress on prefrontal cortex (PFC) synaptic physiology and PFC-mediated functions. Acute/modest stress or chronic/severe stress induces divergent changes on protein kinases, ubiquitin ligases, signaling molecules, and epigenetic enzymes, which leads to the convergent and opposite alterations of postsynaptic glutamate receptors, presynaptic glutamate release, and dendritic spine structure. Consequently, glutamatergic synaptic function in prefrontal cortex is bi-directionally changed, resulting in adaptive or maladaptive effects on cognitive processes. In response to acute stress, executive control can be compromised at the early time point as a result of the promoted emotional reactivity for short-term adaptation, while higher-order cognitive processes are enhanced at later time points for long-term survival.