Ghrelin receptor impairs inhibitory neurotransmission in hippocampal neurons in a ghrelin independent manner

RAINGO, JESICA; MARTÍNEZ DAMONTE, VALENTINA

Congreso; Biannual Meeting of the Federation of European Neuroscience Societies, FENS Forum 2018; 2018

GHSR (Growth Hormone Secretagogue Receptor) is a G-protein coupled receptor that displays high constitutive activity, independent from its endogenous ligand, ghrelin, relying exclusively on GHSR expression levels. It is widely expressed in the nervous system, including regions with restricted ghrelin access, where constitutive activity gains special relevance as the hippocampus. The mechanisms underlying neuronal modulation by GHSR remain elusive. Our previous work demonstrated that presynaptic voltage-gated calcium channels (CaV2) are highly sensitive to GHSR constitutive activity. Presynaptic CaV2 are fundamental structures for neurotransmission, as they allow calcium influx following action potentials which triggers neurotransmitter release. Our aim here was to study the impact of CaV2 modulation by GHSR on hippocampal neurotransmission. We performed electrophysiological recordings in hippocampal primary cultures from E16-18 C57BL6 wild type and GHSR-deficient mice after manipulating GHSR expression levels by lentiviral transduction. We found that GHSR constitutive activity impairs CaV2 native currents, being CaV2.2 the most affected subtype. Moreover we found that GHSR constitutive activity decreases inhibitory but not excitatory post-synaptic currents, without affecting other forms of neurotransmitter release independent of CaV2 activity: miniature post-synaptic currents (frequency or amplitude), as well as the response to a sucrose hyperosmotic shock.We found that GHSR constitutive activity modulates inhibitory neurotransmission in hippocampal neurons through a pre-synaptic mechanism mediated mainly by CaV2.2 currents impairment that specifically affects GABA release. Our work provides insights in assessing the role of this receptor, which has the highest constitutive activity known, in neurotransmission and plasticity at hippocampal synapses.