Ghrelin Boosts Memory Synapses by Hijacking Dopamine Receptors in the Hippocampus

Ghrelin is a 28-amino-acid peptide hormone secreted primarily by the stomach that crosses the blood-brain barrier and acts on growth hormone secretagogue receptors (GHSRs) widely expressed in the hippocampus. While behavioral studies have repeatedly shown ghrelin enhances hippocampal-dependent memory, the precise synaptic and molecular mechanisms have remained poorly defined. This study by Oraegbuna and colleagues at the University of North Dakota provides the most mechanistically detailed account to date of how ghrelin modulates glutamatergic transmission at the perforant path (PP)-dentate gyrus granule cell (GC) synapses — the primary information gateway into the hippocampus.

Using whole-cell patch-clamp recordings from hippocampal slices of 18- to 28-day-old male and female C57BL/6J mice, the researchers applied ghrelin at 100 nM (near-saturating; EC50 = 3.4 nM) and recorded AMPA receptor-mediated excitatory postsynaptic currents (EPSCs). Ghrelin produced a gradual, persistent enhancement of AMPA EPSCs reaching 165 ± 13% of control within approximately 20 minutes (n=16, p=0.0002). This effect was fully blocked by the selective GHSR antagonist [D-Lys3]-GHRP-6 (1 μM), confirming receptor specificity.

Four independent lines of evidence established that ghrelin acts presynaptically to increase glutamate release rather than enhancing postsynaptic receptor function. First, ghrelin significantly reduced the coefficient of variation (CV) of AMPA EPSCs (from 0.18 ± 0.01 to 0.14 ± 0.01, n=13, p=0.007), a hallmark of increased release probability. Second, the paired-pulse ratio fell from 1.48 ± 0.05 to 1.29 ± 0.04 (n=12, p=0.0002), indicating enhanced first-pulse release. Third, ghrelin increased NMDA EPSCs by 195 ± 33% of control (n=9, p=0.021) when recorded in Mg2+-free solution with AMPA receptors blocked. Fourth, miniature EPSC (mEPSC) frequency nearly doubled (0.40 ± 0.07 Hz to 0.79 ± 0.12 Hz, n=13, p=0.002) with no change in amplitude (10.93 ± 0.93 pA vs. 10.66 ± 0.67 pA, p=0.733), confirming a purely presynaptic mechanism. High-frequency stimulation (50 Hz, 20 pulses) further revealed that ghrelin enlarged the readily releasable pool (Nq) to 148 ± 15% of control (n=10, p=0.0002) and increased release probability (Pr) to 119 ± 5% of control (p=0.005).

The study then dissected the intracellular signaling cascade. Contrary to expectation, ghrelin's canonical Gαq-phospholipase C pathway was not required — inhibitors of PLC and PKC did not block the effect. Instead, the PI3K inhibitors LY294002 (10 μM) and wortmannin (200 nM) fully abolished ghrelin-induced AMPA EPSC enhancement. The Gαs protein and the cAMP effector EPAC (exchange protein directly activated by cAMP) were both required, placing the pathway as Gαs → cAMP → EPAC → PI3K. Critically, ghrelin's effect was blocked by the D1 receptor antagonist SCH23390 and absent in D1 receptor knockout tissue, while co-immunoprecipitation confirmed physical association between GHSR and dopamine D1 receptors in mouse hippocampal lysate. This identifies GHSR-D1 receptor heterodimerization as the molecular switch that routes ghrelin signaling through a Gαs-coupled rather than Gαq-coupled pathway in this circuit.

For longevity and brain health, these findings are significant. The dentate gyrus is among the most vulnerable structures in age-related cognitive decline and Alzheimer's disease, and reduced ghrelin signaling has been observed with aging and obesity. By mapping a specific synaptic pathway through which ghrelin sustains excitatory transmission, this work opens new therapeutic angles — including ghrelin mimetics, GHSR-D1 biased agonists, or EPAC activators — that could help preserve memory circuit function in aging populations. Limitations include the use of juvenile mice (18–28 days old) and in vitro slice preparations, which may not fully replicate adult or aging in vivo physiology.