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

Gemma Mcgregor,Jenni Harvey,Andrew J Irving,Adham Farah,Leigh Clements

doi:10.1016/j.neurobiolaging.2018.05.007

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.

Highlights

Hippocampal CA1 pyramidal neurons receive 2 distinct glutamatergic inputs
A second primary antibody was applied to compare GluA1 surface immunostaining relative to phosphorylated JAK2 (p-JAK2), phosphorylated STAT3 (p-STAT3), or PSD-95. p-JAK2 and p-STAT3 staining was visualized by addition of an anti-rabbit Alexa 555econjugated secondary antibody (1:250; Life Technologies, UK) for 30 minutes, whereas an Alexa 569econjugated anti-mouse secondary antibody (1:200; Thermo Fisher, UK) was used to visualize PSD-95 labeling (McGregor et al, 2017)
Leptin markedly influences excitatory synaptic transmission at the anatomically distinct TA input to CA1 pyramidal neurons as leptin induces a novel form of long term potentiation (LTP) at juvenile TA-CA1 synapses (Luo et al, 2015)

Summary

Introduction

Hippocampal CA1 pyramidal neurons receive 2 distinct glutamatergic inputs. The classical trisynaptic pathway innervates apical dendrites in stratum radiatum via indirect inputs from the CA3 region and the Schaffer-collateral (SC) pathway, whereas the temporoammonic (TA) pathway originates in layer III of the entorhinal cortex (EC) and directly innervates dendrites within the stratum lacunosum-moleculare via the perforant path (Aksoy-Askel and Manahan-Vaughan, 2013). Distinct differences in synaptic plasticity mechanisms have been observed at hippocampal SC-CA1 and TA-CA1 synapses (Aksoy-Askel and Manahan-Vaughan, 2013; McGregor et al, 2017). The TA input is thought to contribute to the formation of episodic memories by integrating cortical and place cell information (Nakashiba et al, 2008; Remondes and Schuman, 2004). Histological studies indicate that the TA input undergoes significant morphological changes during ageing, and it is an early target in age-related central nervous system disease as degeneration and loss of synapses occur in this pathway in Alzheimer’s disease (AD) (Braak and Braak, 1996; Yassa et al, 2010)

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Conclusion