(2R,6R)-hydroxynorketamine rapidly potentiates optically-evoked Schaffer collateral synaptic activity.

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) shows rapid and sustained antidepressant effects in preclinical models.
• The precise synaptic mechanisms underlying these antidepressant actions remain under investigation.

Purpose of the Study:

• To investigate whether (2R,6R)-HNK acutely increases glutamate release at Schaffer collateral synapses.
• To explore the role of enhanced glutamate release in the antidepressant-like effects of (2R,6R)-HNK.

Main Methods:

• Optogenetic approach using ChrimsonR expressed in CA3 neurons of Sprague Dawley rats.
• Electrophysiological recordings of CA1 field excitatory postsynaptic potentials (fEPSPs) in transverse brain slices.
• Assessment of synaptic effects of (2R,6R)-HNK (10 μM) on glutamate release probability via paired-pulse facilitation.

Main Results:

• (2R,6R)-HNK rapidly potentiated CA1 fEPSPs evoked by optical stimulation of CA3 afferents.
• This potentiation was linked to an increased glutamate release probability, evidenced by suppressed paired-pulse facilitation.
• The magnitude of potentiation correlated with the suppression of paired-pulse facilitation.

Conclusions:

• (2R,6R)-HNK enhances glutamate release probability at CA1-projecting Schaffer collateral afferents.
• This mechanism likely contributes to the in vivo antidepressant-relevant behavioral effects of (2R,6R)-HNK.
• The study validates optogenetics for studying synaptic plasticity induced by novel antidepressant compounds.