Enhancing Synaptic Plasticity in vitro using Novel Ketamine Derivatives

Abstract

Loss of synaptic plasticity in the brain has been linked to aging‐associated cognitive decline and neurodegeneration, thus providing a promising target for therapeutic interventions. Ketamine, a drug applied for analgesia in emergency medicine and in treatment‐resistant depression, and some of its metabolites rapidly induce synaptic plasticity. However, ketamine cannot be reasonably applied as a neuroprotective agent given its side‐effect profile. With the aim to dissociate pro‐neuroplastic actions from NMDA receptor‐mediated psychotropic side effects we studied novel ketamine derivatives in vitro. We applied ketamine and different ketamine derivatives at various concentrations and incubation durations to primary hippocampal neurons cultivated until maturity of synaptic development. Vesicle‐associated membrane protein 2 (VAMP‐2) immunostaining served as a measure for pre‐synaptic density. For treatment with several candidates, e.g. compound HW‐273, pre‐synapse number was enhanced in a concentration‐dependent manner (Figure 1). Furthermore, enhanced intensity measures of post‐synapse immunostaining for GluA2 (AMPA receptor subunit) in compound‐treated cells indicated elevated AMPA receptor activation at low doses (0.5‐1 µM), whereas for ketamine a higher dose was required for comparable effects (Figure 2). In addition, treatment with high compound concentrations showed no obvious cytotoxic effects, opposite to treatment with ketamine. We conclude that novel ketamine derivatives potently augment neuronal plasticity in a concentration‐dependent fashion. Our study provides preliminary evidence that the potentially beneficial effect on neuronal plasticity can be dissociated from NMDA receptor engagement, which could pave the way for development of new neuroprotective therapies with less unwanted side‐effects.