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Ana Luisa CarvalhoModulation of hippocampal glutamatergic synapses by ghrelin

Abstract :

Peptide hormones such as insulin, leptin and ghrelin are well known for their role in the regulation of appetite.
These peptides, in addition to acting on the hypothalamus to modulate food intake, may play wider roles in modulating brain functions. Recent data show that ghrelin enters the hippocampus, enhancing hippocampal-dependent memory processes; however the mechanisms that underlie the effects of ghrelin are still not understood.   
The ghrelin receptor is expressed in the hippocampus, and is localized to glutamatergic synapses, suggesting a possible role for ghrelin in modulating excitatory transmission. In organotypic hippocampal slices activation of the ghrelin receptor increases the AMPA/NMDA ratio of synaptic responses recorded from CA1 neurons, whereas the NMDA/GABA ratios were found to be unaltered. These results suggest that the ghrelin receptor activation produces a functional change at excitatory CA3-CA1 synapses, and specifically, on AMPA receptor-mediated synaptic transmission. In cultured hippocampal neurons ghrelin receptor activation leads to an increase in the synaptic levels of GluA1-containing AMPA receptors. To directly determine whether ghrelin receptor activation induces the delivery of new AMPARs into synapses, GFP-tagged GluA1 subunit of AMPARs (GluA1-GFP) was expressed in CA1 neurons in organotypic hippocampal slice cultures. Slice treatment with the ghrelin receptor agonist increased the inward rectification of AMPAR-mediated responses in neurons that express GluA1-GFP, strongly suggesting that activation of the orexigenic ghrelin hormone receptor induces synaptic delivery of AMPARs. The delivery of GluA1 into synapses triggered by activation of the ghrelin receptor was blocked by TTX and APV, indicating that it is an activity-dependent process.
Activation of the ghrelin receptor also dramatically enhanced LTP expression in organotypic hippocampal slices, and increased the synaptic accumulation of GluA1 triggered by a chemicalLTP protocol in cultured hippocampal neurons. Lastly, biochemical analysis of organotypical hippocampal slices treated with a ghrelin receptor agonist showed activation of PKC and PKA signaling pathways downstream of the ghrelin receptor activation, leading to changes in the phosphorylation of AMPA receptor subunits and of stargazin. Altogether our data indicate that ghrelin receptor activation enhances synaptic plasticity in the hippocampus by delivering AMPARs into synapses.

Selected publications

Catarino T, Ribeiro LF, Santos SD, Carvalho AL (2012) Regulation of Synapse Composition by Protein Acetylation: The Role of Acetylated Cortactin. J. Cell Science. In Press.

She K, Ferreira JS, Carvalho AL, Craig AM (2012) Glutamate Binding to GluN2B Controls Surface Trafficking of N-Methyl-D-aspartate (NMDA) Receptors. J Biol Chem. 287(33):27432-45.

Santos SD, Iuliano O, Ribeiro L, Veran J, Ferreira JS, Rio P, Mulle C, Duarte CB, Carvalho AL (2012) Contactin associated protein 1 (Caspr1) regulates the traffic and synaptic content of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. J Biol Chem. 287(9):6868-77.

Lobo AC, Gomes JR, Catarino T, Mele M, Fernandez P, Inácio AR, Bahr BA, Santos AE, Wieloch T, Carvalho AL, Duarte CB (2011) Cleavage of the vesicular glutamate transporters under excitotoxic conditions. Neurobiol Dis. 44(3):292-303.

Scientific focus :

Neurons have a complex morphology, with branched dendrites exhibiting thousands of synapses, a specialized region where communication between neurons occurs. We are interested in understanding how these connections between nerve cells are formed and how they are modified with experience. The ability of synapses to change their strength is thought to be the cellular correlate of learning and memory, and synaptic dysfunction is correlated with several neurodegenerative diseases. We focus on excitatory glutamatergic synapses, and study their regulation and formation from a cellular and molecular biology viewpoint. We use a combination of techniques like primary neuronal cultures, biochemistry, molecular and cellular biology to address these questions.

Laurent Ladépêche