Age-dependent regulation of excitatory synaptic transmission at hippocampal temporoammonic-CA1 synapses by leptin

Abstract

The hippocampus is a key target for the hormone leptin and leptin regulation of excitatory synaptic transmission at Schaffer-collateral–CA1 synapses during aging are well documented. However, little is known about the age-dependent actions of leptin at the temporoammonic (TA) input to CA1 neurons. Here we show that leptin induces a novel form of N-methyl-D-aspartate receptor–dependent long-term depression (LTD) at adult (12–24 weeks old) TA-CA1 synapses. Leptin-induced LTD requires activation of canonical Janus tyrosine kinase 2- signal transducer and activator of transcription signaling and removal of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors from synapses. Moreover, leptin-induced LTD is occluded by activity-dependent LTD at TA-CA1 synapses. By contrast, leptin has no effect on excitatory synaptic transmission at aged (12–14 months old) TA-CA1 synapses, and low-frequency stimulation also fails to induce LTD at this age. These findings demonstrate clear age-related alterations in the leptin sensitivity of TA-CA1 synapses and provide valuable information on how the leptin system alters with age. As leptin has been linked to Alzheimer's disease, these findings have important implications for understanding of age-related disorders such as Alzheimer's disease.

Regulation of Hippocampal Synaptic Function by the Metabolic Hormone, Leptin: Implications for Health and Neurodegenerative Disease

“…Recent evidence indicates that the modulatory actions of leptin at excitatory TA-CA1 synapses is also highly dependent on age (McGregor et al, 2018 ; Figure 1 ; Table 1 ). In juvenile tissue, application of leptin leads to TA-CA1 LTP (Luo et al, 2015 ), whereas a persistent depression (LTD) is observed after leptin addition to adult hippocampal slices (McGregor et al, 2018 ). Moreover like SC-CA1 synapses, the leptin-sensitivity of TA-CA1 synapses markedly decreases in aged tissue, as application of leptin fails to induce LTD at aged TA-CA1 synapses (McGregor et al, 2018 ).…”

“…More recent studies indicate that application of leptin also influences the magnitude of excitatory synaptic transmission at another synaptic input to CA1 neurons. This input, which arises in the entorhinal cortex (EC), forms part of the temporoammonic (TA) pathway (Luo et al, 2015 ; McGregor et al, 2018 ; Figure 1 ). Indeed, application of leptin to juvenile (11–18) hippocampal slices induces LTP at this synaptic connection (Luo et al, 2015 ), which directly contrasts with the leptin-induced depression of synaptic transmission observed at SC-CA1 synapses at this age (Moult and Harvey, 2011 ).…”

“…Indeed, application of philanthotoxin also reverses the persistent increase in synaptic transmission induced by leptin at juvenile TA-CA1 synapses, suggesting that GluA2-lacking AMPA receptor are inserted into synapses by leptin and that this process is required for leptin-induced LTP (Luo et al, 2015 ). Conversely, the synaptic removal of GluA2-lacking AMPA receptors is implicated in leptin-induced LTD as leptin fails to induce LTD in the presence of selective inhibitors of clathrin-mediated endocytosis (McGregor et al, 2018 ). In a manner similar to SC-CA1 synapses, application of leptin is not only capable of inducing LTD but this also results in a significant reduction in GluA1 surface expression in hippocampal slices (McGregor et al, 2018 ).…”

“…Conversely, the synaptic removal of GluA2-lacking AMPA receptors is implicated in leptin-induced LTD as leptin fails to induce LTD in the presence of selective inhibitors of clathrin-mediated endocytosis (McGregor et al, 2018 ). In a manner similar to SC-CA1 synapses, application of leptin is not only capable of inducing LTD but this also results in a significant reduction in GluA1 surface expression in hippocampal slices (McGregor et al, 2018 ).…”

“…In juvenile tissue, application of leptin leads to TA-CA1 LTP (Luo et al, 2015 ), whereas a persistent depression (LTD) is observed after leptin addition to adult hippocampal slices (McGregor et al, 2018 ). Moreover like SC-CA1 synapses, the leptin-sensitivity of TA-CA1 synapses markedly decreases in aged tissue, as application of leptin fails to induce LTD at aged TA-CA1 synapses (McGregor et al, 2018 ). It is unclear why leptin has no effect at aged excitatory TA-CA1 synapses.…”