Enhanced ERK activity extends ketamine's antidepressant effects by augmenting synaptic plasticity.

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Psychiatry

Background:

• Repeated ketamine treatment offers rapid antidepressant effects but causes side effects, necessitating strategies for sustained action from single doses.
• Ketamine's antidepressant action is linked to synaptic potentiation at CA3-CA1 synapses, a key neural pathway.

Purpose of the Study:

• To investigate methods for prolonging the antidepressant effects of ketamine by targeting intracellular signaling pathways.
• To explore the role of dual-specificity phosphatases 6 (DUSP6) and extracellular signal-regulated kinase (ERK) in mediating ketamine's sustained effects.

Main Methods:

• Pharmacological inhibition of DUSP6 to enhance ERK activity following ketamine administration.
• Assessment of synaptic potentiation at CA3-CA1 synapses.
• Evaluation of antidepressant-like behavioral effects in animal models.
• Selective deletion of tropomyosin receptor kinase B (TrkB) in excitatory neurons to determine its role.

Main Results:

• Inhibiting DUSP6 augmented ketamine-induced synaptic potentiation at CA3-CA1 synapses.
• DUSP6 inhibition extended the antidepressant-like behavioral effects of ketamine for up to 2 months.
• The effects of DUSP6 inhibition on synaptic and behavioral outcomes were dependent on TrkB signaling in excitatory neurons.

Conclusions:

• Transiently increasing extracellular signal-regulated kinase (ERK) activity via DUSP6 inhibition can sustain ketamine's antidepressant effects.
• Targeting downstream intracellular signaling, specifically TrkB-dependent pathways, offers a promising strategy for prolonging ketamine's therapeutic benefits.
• This approach addresses the clinical need for sustained antidepressant action from single-dose ketamine administration.