Synaptic Plasticity of primary Neurons and Side Effect Assessment following Novel Ketamine Derivative Treatment

Abstract

Throughout spaceflight missions, astronauts are subjected to modifications in the brain such as grey matter compression and changes in cerebrospinal fluid distribution. There are implications that alterations are also operating on a molecular level, i.e., at synaptic terminals, which are critical for cognitive performance during human spaceflight. To counter these changes and ensure safe spaceflight missions, novel pharmaceuticals are being developed that aim to enhance synaptic plasticity. These novel compounds should be administered to astronauts as well as e.g., depression patients on Earth to counteract loss of synaptic contacts and possible cognitive dysfunctions. Ketamines ability to facilitate synaptogenesis and spinogenesis has been demonstrated in various studies. In this thesis, the synaptic plasticity-enhancing effect of novel Ketamine derivatives, which aim to reduce side-effects and have an improved pharmacokinetic profile, have been tested on primary murine hippocampal neuron cultures. To do so, the number of presynaptic boutons was analyzed in mature neurons through the presynaptic marker Synaptobrevin 2 also known as VAMP2 (Vesicle associated membrane protein 2). In addition, potential side effects on other neuronal cell types, i.e., primary murine cortical astrocytes, were examined. Results indicate an increase in presynaptic boutons in treated neurons, which correlate with the administered concentrations. Furthermore, no side effects, such as increased apoptosis or morphological alterations, were observed on astrocytes.