PMC

Model for activity-dependent stimulation of synaptogenesis and spine formation. Synaptic activity and increased glutamate transmission can lead to increased synapse formation and spine density. This occurs through insertion of glutamate-AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors into the postsynaptic membrane. The mechanisms underlying the regulation of synaptogenesis and spine formation have been studied using a cellular model of learning and memory, known as long-term potentiation (LTP). See text for details.

Regulation of mammalian target of rapamycin (mTOR) signalling by NMDA receptor antagonists. Ketamine increases extracellular glutamate, possibly via NMDA receptors on GABAergic interneurons resulting in disinhibition of glutamate transmission. This leads to activity-dependent release of BDNF and stimulation of signalling cascades, including Akt, that activate the mTOR translational system in dendrites of neurons. Induction of translation results in increased levels of GluR1 and other synaptic proteins, providing the machinery required for increased synaptogensis and spine formation. These effects contribute to the rapid and sustained antidepressant actions of ketamine. See text for further details.

Opposing actions of stress and antidepressants on brain-derived neurotrophic factor (BDNF) and neurogenesis. Stress decreases and antidepressant treatment increases the expression of BDNF, as well as vascular endothelial growth factor (VEGF) in the dentate gyrus granule cell layer of the hippocampus. These changes in growth factor expression contribute to the regulation of neurogenesis by stress and antidepressants. The negative effects of stress are also mediated in part by interleukin-1 (IL-1). This model shows the proliferation of neural progenitor cells giving rise to new neurons in the adult hippocampus. Antidepressants influence both the proliferation and survival of new neurons via effects on BDNF and VEGF. See text for details.