Intravascular Ketamine Increases Theta-Burst but Not High Frequency Tetanus Induced LTP at CA3-CA1 Synapses Within Three Hours and Devoid of an Increase in Spine Density

Allie J. Widman, Amy E. Stewart, Elise M. Erb, Elizabeth Gardner, Lori L. McMahon

In the past 20 years, ketamine has become a promising treatment for Major Depressive Disorder (MDD) due to its rapid and sustain antidepressant effects in patients. A single ketamine treatment causes improvement in depressive symptoms within hours and can last weeks, long after it is eliminated. Previous studies have demonstrated increased synaptic plasticity at CA3-CA1 synapses in hippocampus (HPC) 24 h post ketamine treatment suggesting increased activity-dependent hippocampal function may underlie the antidepressant effects of ketamine. If true, these changes should also occur within hours of treatment, a time when symptoms are first alleviated in patients. To determine if augmented synaptic plasticity is observed at an earlier time point, we measured theta-burst and high frequency tetanus induced long-term potentiation (LTP) at CA3-CA1 synapses 3 h following intravenous (IV) ketamine administration. Additionally, we measured basal hippocampal function and spine density to investigate whether connectivity was increased with ketamine treatment. We report that theta-burst but not high frequency tetanus induced LTP is significantly increased 3 h after in vivo ketamine with no changes in basal synaptic function or morphology. Our finding supports increased activity-dependent hippocampal function underlying the antidepressant effects of ketamine as it occurs at a time point that correlates with initial improvements of depressive symptoms in patients.