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Investigators have uncovered a previously unrecognized relationship between a hippocampal dopamine receptor and a ghrelin receptor, which may be involved in hippocampal synaptic plasticity. The results were published in Cell.
“We found in animal models that when these two receptors interact, the ghrelin receptor changes the structure of the dopamine receptor and alters its signaling pathway. This is important because many drugs used currently in the clinic, for example for schizophrenia, have poor compliance because of adverse side effects,” said researcher Roy Smith, PhD, of the Department of Metabolism and Aging at Scripps Research Institute in Jupiter, FL. “This discovery opens the door to using neuronal agents that indirectly modify dopamine signaling by pharmacologically targeting the ghrelin receptor—and potentially dramatically reducing side effects.”
Previous research indicates that the ghrelin receptor (GHSR1a) and dopamine receptor-2 (DRD2) form a heteromer in neurons of the hypothalamus, which is important for food intake suppression. However, the researchers found that although GHSR1a is found in the hippocampus, except for small amounts in the hypothalamus, ghrelin is not detected within the central nervous system. Likewise, it is not completely understood how DRD1 is involved in synaptic plasticity for memory and learning within the hippocampus.
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Smith and colleagues wanted to understand the function of apo-GHSR1a in the hippocampus using hippocampal neurons that expressed both GHSR1a and DRD1 from mice models. They identified dimerization of the DRD1 and apo-GHSR1a receptors and formation of heteromeric complexes of apo-GHSR1a, DRD1, and Gaq. Stimulation by a DRD1 agonist led to synaptic reorganization and markers of synaptic plasticity within the hippocampus. Interestingly, when GHSR1a was inactivated pharmacologically or genetically, the pathway was blocked.
The researchers concluded that “apo-GHSR1a is fundamentally important for dopamine/DRD1-induced initiation of hippocampal synaptic plasticity and formation of hippocampal memory.”
“This concept has potentially profound therapeutic implications, pointing to a possible strategy for selective fine tuning of dopamine signaling in neurons related to memory,” said study author Andras Kern, PhD. “By using small molecules binding to the ghrelin receptor we can enhance or inhibit dopamine signaling.”
