Abstract17ß-estradiol (E2), the most potent form of the steroid hormone class, the estrogens, is a known regulator of hippocampal function and is capable of being synthesised within hippocampal neurons. E2 can modulate glutamatergic synaptic transmission and hippocampal synaptic plasticity, as well as enhance hippocampal dependent learning in rodent models. However, not all effects of estradiol are mediated by the two canonical estrogen receptors, ERa and ERß. Recently, a novel estrogen-sensing G protein coupled receptor (GPR30) was identified, and hippocampal expression of GPR30 indicates a potential role for this receptor in modulating hippocampal function.
Thus, the primary aims of this thesis were to clarify the effects of E2 on glutamatergic synaptic transmission and establish whether activation of GPR30 is involved. Using evoked population EPSP recordings within the dendritic field of hippocampal region CA1, we show that acute application of a physiologically relevant concentration of E2 modulates excitatory synaptic transmission in a bi-directional manner; the most consistent effect however was the induction of a novel form of LTD. Moreover, we show that the GPR30 agonist (G1) mimics the bi-directional effects of E2 on excitatory synaptic transmission. Subsequent characterisation of the E2 and G1 induced LTD revealed that both forms of agonist-induced plasticity are expressed post-synaptically, correlating with findings in hippocampal cultures in which treatment with these agonists resulted in a reduction in the relative density of GluA1-containing AMPA receptors expressed at synapses. In addition, further investigation into the pharmacology of the G1-induced LTD revealed that this effect was not prevented by selective antagonists for GPR30, ERa or ERß, however could be attenuated by a selective estrogen receptor downregulator and putative ligand for GPR30, ICI 182 780. Furthermore, we establish that in hippocampal neurons, the G1-induced reduction in surface AMPA receptor expression is mediated via the ERK 1/2 signalling pathway.
In summary, the data presented here suggests that at CA3 to CA1 synapses, E2 and the GPR30 agonist can induce a novel form of LTD in adult hippocampal tissue. Considering the multifaceted role of estrogens in human physiology, pharmaceuticals which modulate this system in a site specific manner (either by influencing estrogen synthesis or targeting estrogen receptors) could be of benefit in hippocampal dependent learning and memory processes in health and disease.
|Date of Award
|Andrew Irving (Supervisor) & Jenni Harvey (Supervisor)