Synaptogenesis is the formation of new synapses between neurons in the brain. This process is critical for neural plasticity, learning, and memory.

Research shows that ketamine rapidly increases synaptogenesis in the prefrontal cortex and hippocampus. It does this in several key ways:

  • Ketamine increases brain-derived neurotrophic factor (BDNF). BDNF supports long-term potentiation – the strengthening of synapses based on patterns of neural activity. BDNF facilitates synaptic plasticity1.
  • Ketamine also activates the mTOR pathway. mTOR signaling promotes the translation of synaptic proteins needed to produce new synapses2.
  • The new synapse formation induced by ketamine occurs via synthesizing synaptic proteins like PSD-95, glutamate receptors, and synapsin. This leads to increased density and function of synapses3.
  • Ketamine also increases the number of mature mushroom-shaped dendritic spines, the sites where synapses form. This further enables synaptogenesis.

The surge in synaptogenesis induced by ketamine enhances connectivity and communication between neurons in brain regions involved in mood and depression. This may rapidly “rewire” dysfunctional circuits and restore synaptic plasticity impaired by stress and depression. The sustained increase in connections then contributes to the long-lasting antidepressant effects seen with ketamine.

  1. Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS. BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol. 2014;18(1):pyu033.
  2. Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-964.
  3. Moda-Sava RN, Murata Y, Bourg J, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364(6436):eaat8078.

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