Stress and remodeling of hippocampal spine synapses

By nature's original design, stress is a protective mechanism, signaling danger to homeostasis and, as a result, stimulating the brain to initiate coping and adaptive responses, which ultimately increases the chances of survival. On the other hand, stress may become a danger to homeostasis itself, when it is so severe or so prolonged that it overpowers cellular reserves. One of the consequences of traumatic stress is loss of hippocampal spine synapses, which is the main topic of this chapter summarizing research findings from the last 10+ years. Loss of spine synapses is thought to be a neuronal defense mechanism against excitotoxic damage, so the subcellular mechanisms of synapse loss are reviewed in the context of glutamatergic insults. One of the main conceptual derivates of stress-induced synaptic alterations is the "synaptogenic" hypothesis of major depressive disorder. The synaptogenic hypothesis postulates an inverse correlation between the number of limbic, mainly prefrontal cortical and hippocampal, spine synapses and the severity of depressive behavior/symptoms. The synaptogenic hypothesis implies that synaptoprotective interventions, that are capable of countering the stress-induced loss of limbic spine synapses, are probably also capable of promoting stress resilience, which may provide the conceptual basis for a preventive approach in antidepressant therapy. Finally, we discuss why electron microscopic stereology is a reliable and highly accurate technique for the quantitative assessment of ultrastructural particulate objects, such as spines and synapses.