Study identifies previously unknown mechanism of memory formation in the brain.


Ghrelin is a peptide released from the empty stomach into circulation, and which acts on the brain to promote appetite. Recent studies showed that ghrelin also affects learning and memory, however, the mechanism for this effect is unknown.  Now, a study from researchers at The Scripps Research Institute (TSRI) has shown that a previously unknown interaction between the proteins grehlin and dopamine has a substantial effect on memory formation.  The team state that their findings could have implications for future drug discovery efforts for a number of neurodegenerative diseases.  The opensource study is published in the journal Cell.

Previous studies show that activation of ghrelin receptors in the hippocampus enhances synaptic signaling by glutamate, the major excitatory neurotransmitter in the brain. Ghrelin promotes the synaptic accumulation of glutamate receptors of the AMPA subtype, and increases long-term potentiation, one form of synaptic plasticity that is thought to underlie learning and memory. These effects are guided largely by the expression of the ghrelin receptor growth hormone secretagogue type 1a (GHS-R1a) in the hypothalamus and pituitary, with GHS-R1a being shown as expressed in other brain regions, including the hippocampus, where its activation enhances memory retention.  However, despite broad expression of GHSR1a in the CNS, other than trace amounts in the hypothalamus, ghrelin is undetectable in the brain making difficult to map it’s function in memory.  Despite this, subsets of hypothalamic neurons that regulate appetite were identified that co-express GHSR1a and dopamine receptors, suggesting a link between the two proteins.

The current study used animal models to focus on the two receptors, dopamine and ghrelin.  Results show that when these two receptors interact, the ghrelin receptor changes the structure of the dopamine receptor and alters its signaling pathway.  Data findings show that the biologically active ghrelin-dopamine receptor complex produces synaptic plasticity, the ability of the brain’s synapses to grow and expand, the biological process underpinning long-term memory formation.

Results show that when the group blocked the ghrelin receptor, dopamine-dependent memory formation was inhibited in animal models, demonstrating that the mechanism is essential to that process.  The team conclude that interaction between a dopamine receptor and a ghrelin receptor (that is not liganded to ghrelin) initiates a non-canonical, cAMP-independent signaling pathway that regulates dopaminergic regulation of hippocampal memory.

The lab explain that this opens the door to using neuronal agents that indirectly modify dopamine signaling by pharmacologically targeting the ghrelin receptor, and potentially dramatically reducing side effects.  They go on to hypothesize that this has therapeutic implications pointing to a possible strategy for selective fine-tuning of dopamine signaling in neurons related to memory, enhancing or inhibiting dopamine signaling by using small molecules to bind to the ghrelin receptor.

The team surmise that their findings further expands the ghrelin receptor’s importance with animal models showing that ghrelin inhibits neuronal loss associated with Parkinson’s disease, and stroke.  For the future, the researchers state that ghrelin has a possible role in treating memory loss, age related or otherwise.

Source: Florida campus of The Scripps Research Institute (TSRI)

 

The ghrelin receptor (GHSR1a) and dopamine receptor-1 (DRD1) are coexpressed in hippocampal neurons, yet ghrelin is undetectable in the hippocampus; therefore, we sought a function for apo-GHSR1a. Real-time single-molecule analysis on hippocampal neurons revealed dimerization between apo-GHSR1a and DRD1 that is enhanced by DRD1 agonism. In addition, proximity measurements support formation of preassembled apo-GHSR1a:DRD1:Gαq heteromeric complexes in hippocampal neurons. Activation by a DRD1 agonist produced non-canonical signal transduction via Gαq-PLC-IP3-Ca2+ at the expense of canonical DRD1 Gαs cAMP signaling to result in CaMKII activation, glutamate receptor exocytosis, synaptic reorganization, and expression of early markers of hippocampal synaptic plasticity. Remarkably, this pathway is blocked by genetic or pharmacological inactivation of GHSR1a. In mice, GHSR1a inactivation inhibits DRD1-mediated hippocampal behavior and memory. Our findings identify a previously unrecognized mechanism essential for DRD1 initiation of hippocampal synaptic plasticity that is dependent on GHSR1a, and independent of cAMP signaling.  Hippocampal Dopamine/DRD1 Signaling Dependent on the Ghrelin Receptor.  Smith et al 2015.

The ghrelin receptor (GHSR1a) and dopamine receptor-1 (DRD1) are coexpressed in hippocampal neurons, yet ghrelin is undetectable in the hippocampus; therefore, we sought a function for apo-GHSR1a. Real-time single-molecule analysis on hippocampal neurons revealed dimerization between apo-GHSR1a and DRD1 that is enhanced by DRD1 agonism. In addition, proximity measurements support formation of preassembled apo-GHSR1a:DRD1:Gαq heteromeric complexes in hippocampal neurons. Activation by a DRD1 agonist produced non-canonical signal transduction via Gαq-PLC-IP3-Ca2+ at the expense of canonical DRD1 Gαs cAMP signaling to result in CaMKII activation, glutamate receptor exocytosis, synaptic reorganization, and expression of early markers of hippocampal synaptic plasticity. Remarkably, this pathway is blocked by genetic or pharmacological inactivation of GHSR1a. In mice, GHSR1a inactivation inhibits DRD1-mediated hippocampal behavior and memory. Our findings identify a previously unrecognized mechanism essential for DRD1 initiation of hippocampal synaptic plasticity that is dependent on GHSR1a, and independent of cAMP signaling. Hippocampal Dopamine/DRD1 Signaling Dependent on the Ghrelin Receptor. Smith et al 2015.

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