Abstract
The hormone estrogen is believed to be an important modulator of hippocampal synaptic plasticity and function. The actions of estrogen at hippocampal Schaffer-collateral (SC)-CA1 synapses has been described in detail and at these synapses, estrogen can rapidly potentiate excitatory synaptic transmission (Oberlander and Woolley., 2017). The actions of estrogen at the anatomically distinct Temporoammonic (TA)-CA1 synapse is not as well established, however initial studies indicate that estrogen can robustly enhance synaptic transmission at this synapse (Smith et al., 2016). Therefore, the aim of this project was to investigate the actions of estrogen and its receptors on excitatory synaptic transmission at juvenile TA-CA1 synapses. The results presented in this thesis demonstrate that estradiol (E2) can induce a robust LTP at juvenile TA-CA1 synapses. E2-induced LTP at these synapses involves activation of ERα and GPER1 as selective agonists of these receptors mimic the effects of E2 at TA-CA1 synapses. However, E2-induced LTP does not involve ERβ, and ERβ-selective agonists do not alter excitatory synaptic transmission at TA-CA1 synapses. ERα-mediated LTP and GPER1-mediated LTP require activation of NMDA receptors, involve the insertion of GluA2-lacking AMPA receptors and have a post-synaptic mechanism of action. Despite sharing commonalities in their mechanism ERα-mediated LTP and GPER1-mediated LTP utilise distinct signalling mechanisms - ERα-mediated LTP involves PI3-K signalling whereas GPER1-mediated LTP involves ERK signalling and transactivation of EGFR. Further, ERα, GPER1 and hippocampal-synthesised E2 have been implicated in the induction of activity-dependent LTP at TA-CA1 synapses highlighting the crucial role that both hormone and receptor play in regulating synaptic plasticity at TA-CA1 synapses. The TA pathway reportedly undergoes morphological and plasticity changes in models of Alzheimer’s disease (Yassa et al., 2010; Maurin et al., 2014; Booth et al., 2016) and it has been suggested that estrogen may offer neuroprotective actions in models of AD, however, the exact contributions of GPER1 are unclear. This thesis identifies that GPER1 exert neuroprotective actions against Aβ-mediated synaptic disruption and AMPA receptor internalisation.Therefore, the data presented in this thesis highlight that estrogen and its receptors not only play a role in modulating synaptic plasticity at juvenile TA-CA1 synapses but also offer neuroprotection against Aβ-mediated synaptic impairments and thus, may be regarded as targets that can benefit CNS health and disease.
| Date of Award | 2020 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Jenni Harvey (Supervisor) & Sheriar Hormuzdi (Supervisor) |