Dopamine D4 receptor activation restores CA1 LTP in hippocampal slices from aged mice.

Fangli Guo,Zhiwei Feng,Martin Vreugdenhil,Dandan Zhao,Xiaofang Wang,Jianhua Zhao,Jiangang Wang,Chengbiao Lu

doi:10.1111/acel.12666

Fangli Guo, Zhiwei Feng + Show 6 more

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https://doi.org/10.1111/acel.12666

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Abstract

SummaryNormal aging is characterized with a decline in hippocampal memory functions that is associated with changes in long‐term potentiation (LTP) of the CA3‐to‐CA1 synapse. Age‐related deficit of the dopaminergic system may contribute to impairment of CA1 LTP. Here we assessed how the modulation of CA1 LTP by dopamine is affected by aging and how it is dependent on the Ca2+ source. In slices from adult mice, the initial slope of the field potential showed strong LTP, but in slices from aged mice LTP was impaired. Dopamine did not affect LTP in adult slices, but enhanced LTP in aged slices. The dopamine D1/D5 receptor (D1R/D5R) agonist SKF‐81297 did not affect LTP in adult but caused a relative small increase in LTP in aged slices; however, although there was no difference in dopamine D4 receptor (D4R) expression, the D4R agonist PD168077 increased LTP in aged slices to a magnitude similar to that in adult slices. The N‐Methyl‐D‐aspartate receptor antagonist D‐AP5 reduced LTP in adult slices, but not in aged slices. However, in the presence of D‐AP5, PD168077 completely blocked LTP in aged slices. The voltage‐dependent calcium channel (VDCC) blocker nifedipine reduced LTP in adult slices, but surprisingly enhanced LTP in aged slices. Furthermore, in the presence of nifedipine, PD168077 caused a strong enhancement of LTP in aged slices to a magnitude exceeding LTP in adult slices. Our results indicate that the full rescue of impaired LTP in aging by the selective D4R activation and that a large potentiation role on LTP by co‐application of D4R agonist and VDCC blocker may provide novel strategies for the intervention of cognitive decline of aging and age‐related diseases.

Highlights

Normal brain aging is characterized by the decline in cognitive performance that includes modules dependent on hippocampal function, which has been linked to changes in long-term potentiation (LTP) of synaptic strength in the hippocampus. (Shankar et al, 1998; Hsu et al, 2002; Rosenzweig & Barnes, 2003; Foster, 2007; Kumar, 2011)
LTP of the Schaffer collateral (SC)-CA1 synapse decreases with normal brain aging when using low-intensity LTP induction protocols that mainly rely on Ca2+ influx through N-Methyl-D-aspartate receptors (NMDARs) (Hsu et al, 2002), but not when high-intensity protocols are used (Kumar, 2011)
To test whether aging affects the dopaminergic modulation of synaptic plasticity in a Ca2+ influx-dependent way, we examined the effect of selective dopamine receptor (DR) agonists on hippocampal CA1 LTP in the presence of NMDA receptor antagonist or voltagedependent calcium channel (VDCC) blocker

Summary

Introduction

Normal brain aging is characterized by the decline in cognitive performance that includes modules dependent on hippocampal function, which has been linked to changes in long-term potentiation (LTP) of synaptic strength in the hippocampus. (Shankar et al, 1998; Hsu et al, 2002; Rosenzweig & Barnes, 2003; Foster, 2007; Kumar, 2011). LTP of the Schaffer collateral (SC)-CA1 synapse decreases with normal brain aging when using low-intensity LTP induction protocols that mainly rely on Ca2+ influx through N-Methyl-D-aspartate receptors (NMDARs) (Hsu et al, 2002), but not when high-intensity protocols are used (Kumar, 2011). The aging-dependent increase in expression and function of voltage-dependent calcium channels (VDCCs) in CA1 pyramidal neurons is thought to cause inhibition of N-Methyl-D-aspartate receptors (NMDARs) (Norris et al, 1996; Shankar et al, 1998). Aging is associated with a shift in synaptic plasticity from NMDARdependent mechanisms to VDCC-dependent mechanisms (Shankar et al, 1998; Foster, 2007; Kumar, 2011). Whereas Hernandez et al (2014) report an aging-related increase in the expression of dopamine D2, D3, and D5 receptors, others found a decrease in the expression of dopamine receptors in the hippocampus from humans and rodents (Amenta et al, 2001; Hemby et al, 2003; Backman et al, 2006)

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