Therapeutic ketamine has been shown to impact synapses and dendrites in the brain, which may contribute to its cognitive and antidepressant effects. The primary mechanism by which ketamine is believed to exert its therapeutic effects is by modulating the glutamatergic system, particularly by blocking N-methyl-D-aspartate (NMDA) receptors.
- Synaptic plasticity: Ketamine has been found to enhance synaptic plasticity, which refers to the ability of synapses (the connections between neurons) to change in strength or function. This effect is thought to be mediated by an increase in the release of the neurotransmitter glutamate, which subsequently activates a different type of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor. This AMPA receptor activation produces a cascade of intracellular signaling events promoting synaptic plasticity.
- Dendritic spine growth: Ketamine has been shown to promote the development of dendritic spines, small protrusions on dendrites that receive synaptic input from other neurons. This effect may enhance the connectivity between neurons and improve the overall function of neural networks involved in mood regulation and cognition.
- Neurotrophic factor release: Ketamine has been found to increase the release of brain-derived neurotrophic factor (BDNF). This protein supports the survival and growth of neurons and is crucial for neuroplasticity. BDNF plays a key role in dendritic spine formation, maturation, and maintenance, contributing to improved neural circuit connectivity and function. Higher levels of BDNF have been associated with better cognitive performance and mood regulation.
- Neurogenesis: Ketamine has also been shown to promote neurogenesis, which generates new neurons. This can lead to improved neuronal connectivity, enhanced cognitive function, and better mood regulation. Neurogenesis is particularly relevant in the hippocampus, a brain region involved in learning, memory, and mood regulation, where ketamine has been found to promote the growth of new neurons.
- These effects of ketamine on synapses and dendrites are believed to contribute to its rapid antidepressant and cognitive-enhancing effects. By improving synaptic plasticity, dendritic spine growth, and neurogenesis, ketamine may help strengthen and restore impaired neural networks in conditions such as depression, ultimately leading to improved cognition and mood.
The rapid effects of ketamine on synapses and dendrites and its influence on neurotrophic factors like BDNF offer promising therapeutic potential for various mental health conditions. Further research is needed to understand the long-term cognitive effects of ketamine therapy and to develop more targeted and refined treatment approaches for individuals suffering from mental health disorders.
Duman, R. S., & Aghajanian, G. K. (2012). Synaptic dysfunction in depression: potential therapeutic targets. Science, 338(6103), 68-72. Retrieved from https://science.sciencemag.org/content/338/6103/68
Li, N., Lee, B., Liu, R. J., Banasr, M., Dwyer, J. M., Iwata, M., … & Aghajanian, G. K. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science, 329(5994), 959-964. Retrieved from https://science.sciencemag.org/content/329/5994/959
Zanos, P., & Gould, T. D (2018). Mechanisms of ketamine action as an antidepressant. Molecular psychiatry, 23(4), 801-811. Retrieved from https://www.nature.com/articles/mp201740
Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P., … & Monteggia, L. M. (2011). NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature, 475(7354), 91-95. Retrieved from https://www.nature.com/articles/nature10130