The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders

Stress is a primary risk factor for several neuropsychiatric disorders. Evidence from preclinical models and clinical studies of depression have revealed an array of structural and functional maladaptive changes, whereby adverse environmental factors shape the brain. These changes, observed from the molecular and transcriptional levels through to large-scale brain networks, to the behaviours reveal a complex matrix of interrelated pathophysiological processes that differ between sexes, providing insight into the potential underpinnings of the sex bias of neuropsychiatric disorders. Although many preclinical studies use chronic stress protocols, long-term changes are also induced by acute exposure to traumatic stress, opening a path to identify determinants of resilient versus susceptible responses to both acute and chronic stress. Epigenetic regulation of gene expression has emerged as a key player underlying the persistent impact of stress on the brain. Indeed, histone modification, DNA methylation and microRNAs are closely involved in many aspects of the stress response and reveal the glutamate system as a key player. The success of ketamine has stimulated a whole line of research and development on drugs directly or indirectly targeting glutamate function. However, the challenge of translating the emerging understanding of stress pathophysiology into effective clinical treatments remains a major challenge.