Characterization of de novo generated synapses in the adult brain – effects of melanocortin receptor activation

Abstract

Characterization of de novo generated synapses in the adult brain – effects of melanocortin receptor activation ABSTRACT Oskar Hjerne Sundbaum Degree project, Programme in Medicine Supervisor: Joakim Strandberg, M.D., Ph.D. Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg Gothenburg, Sweden, 2017 Introduction In neurodegenerative diseases, there is a loss of synapses due to excessive elimination. On the other hand, formation of new synapses is increased by certain anti-depressants and endogenous hormones, including the melanocortin-4 receptor agonist melanotan II (MTII). In the developing brain, newly formed synapses are AMPA-silent (i.e. they lack functional AMPA signaling), whereas not much is known about newly formed synapses in the adult brain. The aim of this study was to induce formation of new synapses in the adult hippocampus using MTII, and to investigate if these de novo generated synapses are AMPA-silent. Materials and Methods Hippocampal slices from adult rats were treated with MTII (by either incubation or wash-in) for 1-3 hours. Extracellular field recordings with stimulation at test-pulse frequency (0.2 Hz) were performed in the hippocampal CA1 region, and the magnitude of the field excitatory postsynaptic potential (fEPSP) was measured. Results During test-pulse stimulation for 10 minutes, fEPSP magnitude decreased by ~ 15 %. The decrease was fully reversed by 20 minutes of inactivity, and was induced again by further stimulation. Wash-in of MTII led to an initial increase in fEPSP magnitude by ~ 40 %, and a subsequent decrease of ~ 15 % during test-pulse stimulation. Conclusions MTII induced a synaptic depression in the adult hippocampus resembling that in the developing hippocampus, i.e. induced by very low frequency stimulation (0.2 Hz) and showing full recovery upon inactivity. This depression is likely due to loss of functional AMPA signaling in newly formed synapses. The mismatch in potentiation by wash-in of MTII and the subsequent depression by test-pulse stimulation is likely explained by an increased number of AMPA receptors in existing synapses. Keywords: AMPA receptor, hippocampus, neurodegeneration, silent synapse, synaptic depression