The reemergence of long-term potentiation in aged Alzheimer’s disease mouse model

Seonghoo Huh,Byeong C Kim,Kun Ho Lee,Man-Seok Park,Soo-Ji Baek,Dong Hyun Kim,Jihoon Jo,Seong-Min Choi,Kyung-Hwa Lee,Daniel J Whitcomb

doi:10.1038/srep29152

Abstract

Mouse models of Alzheimer’s disease (AD) have been developed to study the pathophysiology of amyloid β protein (Aβ) toxicity, which is thought to cause severe clinical symptoms such as memory impairment in AD patients. However, inconsistencies exist between studies using these animal models, specifically in terms of the effects on synaptic plasticity, a major cellular model of learning and memory. Whereas some studies find impairments in plasticity in these models, others do not. We show that long-term potentiation (LTP), in the CA1 region of hippocampal slices from this mouse, is impared at Tg2576 adult 6–7 months old. However, LTP is inducible again in slices taken from Tg2576 aged 14–19 months old. In the aged Tg2576, we found that the percentage of parvalbumin (PV)-expressing interneurons in hippocampal CA1-3 region is significantly decreased, and LTP inhibition or reversal mediated by NRG1/ErbB signaling, which requires ErbB4 receptors in PV interneurons, is impaired. Inhibition of ErbB receptor kinase in adult Tg2576 restores LTP but impairs depotentiation as shown in aged Tg2576. Our study suggests that hippocampal LTP reemerges in aged Tg2576. However, this reemerged LTP is an insuppressible form due to impaired NRG1/ErbB signaling, possibly through the loss of PV interneurons.

Highlights

One explanation for these age-dependent effects could relate to the interneuronal control of pyramidal neurons
Both ErbB receptor kinases in GABAergic interneurons and the endogenous ligand neuregulin 1 (NRG1), a neurotropic factor implicated in neural development, neurotransmission and synaptic plasticity[25], have been variously shown to regulate hippocampal long-term potentiation (LTP): (1) neutralization of endogenous NRG1 in the hippocampus enhances the magnitude of hippocampal LTP at CA1 region[26], whereas addition of exogenous NRG1 suppresses the induction of LTP27,28; (2) inhibition of ErbB4 kinase increases the magnitude of hippocampal LTP, an effect observed in ErbB4 knockout mice[29,30]; (3) ErbB4 is selectively expressed in interneurons but not in pyramidal neurons[31], and ErbB4 deletion in parvalbumin (PV) interneurons, the major type of GABAergic interneurons in hippocampus[32,33], completely blocks the LTP regulation induced by NRG126,30
Increased field excitatory postsynaptic potentials (fEPSP) induced by high frequency stimulation (HFS) at the Schaffer collateral pathway was maintained for 2 hours in adult littermate wild type (WT), but returned to baseline levels in adult Tg2576 (Tg: 113.2 ± 7.4% of baseline, n = 8, closed circle; WT: 159.1 ± 9.4%, n = 8, open circle, P < 0.01 Fig. 1A), which is consistent with reports describing impaired LTP in Tg2576 of similar ages[12,15]

Summary

Introduction

One explanation for these age-dependent effects could relate to the interneuronal control of pyramidal neurons. One possible explanation is that the age-dependent loss of GABAergic interneurons in the transgenic mice serves to facilitate the induction of LTP in the hippocampal CA1 region Both ErbB receptor kinases in GABAergic interneurons and the endogenous ligand neuregulin 1 (NRG1), a neurotropic factor implicated in neural development, neurotransmission and synaptic plasticity[25], have been variously shown to regulate hippocampal LTP: (1) neutralization of endogenous NRG1 in the hippocampus enhances the magnitude of hippocampal LTP at CA1 region[26], whereas addition of exogenous NRG1 suppresses the induction of LTP27,28; (2) inhibition of ErbB4 kinase increases the magnitude of hippocampal LTP, an effect observed in ErbB4 knockout mice[29,30]; (3) ErbB4 is selectively expressed in interneurons but not in pyramidal neurons[31], and ErbB4 deletion in parvalbumin (PV) interneurons, the major type of GABAergic interneurons in hippocampus[32,33], completely blocks the LTP regulation induced by NRG126,30. We demonstrate a possible link between a loss of interneurons, NRG1/ErbB signaling dysregulation and changes in synaptic plasticity in a mouse model of AD

Methods

Results

Conclusion