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Title: Age-dependent regulation of hippocampal excitatory synaptic transmission by leptin
Author: Mcgregor, Gemma
Awarding Body: University of Dundee
Current Institution: University of Dundee
Date of Award: 2018
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There is extensive evidence to suggest that the adipocyte-derived hormone, leptin is a diverse regulator of hippocampal synaptic function (Irving and Harvey, 2014). Previous studies demonstrate that leptin can regulate hippocampal excitatory synaptic transmission in an age-dependent manner at Schaffer collateral (SC)-CA1 synapses (Moult and Harvey, 2011). In addition, recent evidence indicates that leptin can also regulate synaptic transmission at the anatomically distinct input to CA1 neurons, the temporoammonic (TA) synapse (Luo et al., 2015). Therefore, the aim of this study was to investigate the age-dependent effects of leptin on excitatory synaptic transmission at TA-CA1 synapses. These findings show that in accordance with previous studies (Luo et al., 2015), leptin induces long term potentiation (LTP) at TA-CA1 synapses in juvenile hippocampus. This effect of leptin contrasts with synaptic depression evoked by leptin at juvenile SC-CA1 synapses (Moult and Harvey, 2011). Moreover, from this study it was shown that at adult TA-CA1 synapses, leptin induces long term depression (LTD), thus, indicating that the effect of leptin on synaptic transmission at TA-CA1 synapses reverses with age. In addition, leptin-induced LTD at adult TA-CA1 synapses contrasts with the previously reported actions of leptin at SC-CA1 synapses in adult hippocampus (Moult and Harvey, 2011). Therefore, not only does leptin act in an age-dependent manner at both TA-CA1 and SC-CA1 synapses, but leptin exerts distinct actions at the two inputs into the CA1 region. The signalling mechanisms that underlie leptin-induced LTD at adult TA-CA1 synapses displays parallels with activity-dependent LTD at adult TA-CA1 synapses. Interestingly, unlike SC-CA1 synapses, activity-dependent LTD is readily observed at adult TA-CA1 synapses. In addition, in aged hippocampus, leptin fails to significantly alter excitatory synaptic transmission at TA-CA1 synapses, thus, suggesting that ageing perturbs the actions of leptin at this synapse. Moreover, in juvenile hippocampus, similarly to SC-CA1 synapses (Doherty et al., 2013; Malekizadeh et al., 2016), leptin is neuroprotective against the detrimental effects of amyloid β (Aβ); a pathological hallmark of Alzheimer's disease (AD), on synaptic transmission at TA-CA1 synapses. Therefore, it is feasible that leptin has therapeutic potential in AD. Emerging evidence suggests that the TA-CA1 synapse is important for the retention and retrieval of long term consolidated memories, thus, as leptin can regulate excitatory synaptic transmission at TA-CA1 synapses in an age-dependent manner, this is likely to have important implications in leptin's role in ageing and disease.
Supervisor: Harvey, Jenni ; Irving, Andrew J. Sponsor: BBSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Leptin ; Hippocampus ; Synaptic transmission ; Synaptic plasticity ; Excitatory ; Age-dependent