Fig. 4

Psychological Stress: Noradrenergic Signalling and Synaptic Plasticity. A crucial part in memory formation belongs to synaptic activity/plasticity, particularly in the hippocampus. First, in the axon of a neuron, [1] action potentiation converts electrical stimuli into a chemical message [glutamate] to pass it through the synapse to the dendrite of another neuron. At the dendritic spine, ionotropic channels [2a] NMDA- and [2b] AMPA-type glutamate receptors “receive the message”. [3a] NMDA receptors facilitate Ca²⁺ entry that triggers Ca²⁺/Calmodulin dependent kinases Iiα, which results in synaptic incorporation of AMPA receptors—a necessary mechanism for long-term potentiation as a part of memory formation. [3b] Activated AMPA receptors stimulate ERK (aka MAPK). Additionally, in the dorsal hippocampus, activated estrogen receptors can stimulate GluA1 subunit via ERK linked to enhanced neurocognition in females but not in males. During acute stress (depicted by black double arrows), due to emotional arousal (e.g., fear), released norepinephrine binds to β2-adrenoreceptors (G-protein-coupled receptor) and activates protein Gαs; that stimulates adenylate cyclase and cAMP synthesis, which accumulation triggers protein kinase A and ERK/MAPK (depicted by yellow ovals, see Fig. 1 for more details). Protein kinase A activates AMPA receptor by its subunit GluA1 phosphorylation that results in the AMPA receptor’s trafficking and synaptic incorporation. As well, protein kinase A activates Ca²⁺/Calmodulin dependent kinases IIα directly and via [4] stimulation of L-type Ca²⁺ channel that increases Ca²⁺ influx and activates the kinases further (white arrows depict Ca²⁺ signalling). During severe stress, excessive norepinephrine release can also [5] activate α₁-adrenoreceptors and trigger protein kinase C signalling that activates AMPA receptors. Stathmin is a microtubule-stabilizing and ERK-regulated protein that displays cytoprotective function. Specifically, dynamical changes in the microtubule stability are vital for synaptic plasticity and long-term potentiation. Synaptic input, such as during learning/facing a threat, hyperactivates stathmin, which decreases microtubule stability (depolymerization within first hour). SNARE protein complexes interact with serotonin signalling regulated by fkbp5 gene (see Fig. 3), that potentially can determine an individual’s susceptibility to stress and depression. cAMP, cyclic AMP; CREB, cAMP response element-binding protein; ERK, extracellular regulated kinase, aka mitogen-activated protein kinase (MAPK); GR, glucocorticoid receptors; GRE, glucocorticoid response elements; PO₃², phosphorylation