Date of Award

August 2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Saobo Lei

Abstract

The dentate gyrus (DG) and medial entorhinal cortex (MEC) are critical regions of the limbic system involved in spatial navigation, pattern separation, neurogenesis, learning and memory, and mood regulation. Alterations within the DG circuitry have been implicated in cognitive impairments in Alzheimer’s disease (AD), schizophrenia, major depressive disorder, and temporal lobe epilepsy. Disruption in the MEC is associated with the onset of AD pathology, temporal lobe epilepsy and schizophrenia. The roles of the DG and MEC in health and disease are mediated by their precise cellular activity. The main neurons of the DG are the glutamatergic granule cells (GCs) and the GABAergic interneurons. The MEC on the other hand is made up majorly of the excitatory principal neurons that are glutamatergic and the local inhibitory interneurons, which are GABAergic. This dissertation is composed of four aims related to the roles of neuropeptides and G protein-coupled receptors (GPCRs) in modulating activity of the DG and MEC neurons and influencing neurotransmission at the synapses between the DG and MEC. The first aim examines how ghrelin modulates alters synaptic transmission at the perforant path-granule cells (PP-GC) synapses. The second aim will test how ghrelin affects DG GC excitability and influences spatial memory. The third aim investigates how the G protein coupled receptor 40 (GPR40) alters neuronal activity in DG GCs and contributes to fear memory formation. The fourth aim addresses the roles and mechanisms of GPR40 in the MEC and in spatial learning.

For Study 1, activation of the ghrelin receptors at the PP-GC synapses facilitated glutamatergic signaling by increasing the pool of vesicles at the presynaptic terminal and activating the dopamine D1 receptors. Increase in glutamate release was mediated by the cAMP/EPAC/PI3K pathway.

For Study 2, bath application of ghrelin increased the excitability of the DG GCs via the depression of the inwardly rectifying K+ channels (Kir). Ghrelin-induced excitation was further determined to be dependent on the presence of cyclic AMP (cAMP) and the exchange protein directly activated by cyclic AMP (EPAC). Furthermore, microinjection of ghrelin into the DG dose-dependently enhanced spatial working memory on the Y maze spontaneous alternation test.

For Study 3, activation of GPR40 excited the cells of the DG. Action potential numbers elicited by GPR40 activation required phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K). GPR40-mediated excitation was dependent on the depression of a Kir channel and activation of multiple cation channels including a non selective cation channel. GPR40 activation increased Long-term Potentiation (LTP) induction at the PP-GC and this effect was mediated by protein kinases A and C. Systemic administration of the GPR40 agonist facilitated contextual fear memory and improved cued fear extinction.

For Study 4, application of the GPR40 agonist increased neuronal excitability within the MEC by depressing a Kir channel and activating a cation channel. Furthermore, GPR40-induced excitation required the functions of PLC, inositol 1,4,5 trisphosphate (IP3) receptors and Ca2+ from intracellular stores. Activation of the cation channels by GPR40 was mediated by IP3 receptors and Ca2+ from the endoplasmic reticulum whilst depression of Kir channels required basal cytosolic Ca2+ levels. Peripheral injection of the GPR40 agonist increased the number of correct choices made on the radial arm maze, which is indicative of an improvement in spatial learning.

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