Amyloid \u03b2 causes excitation/inhibition imbalance through dopamine receptor 1-dependent disruption of fast-spiking GABAergic input in anterior cingulate cortex

Si-Qiang Ren,Jing-Zhi Yan,Zaohuo Cheng,Chunhui Jin,Jia-Jun Yin,Wen Yao,Jianmin Yuan,Shui Yu

doi:10.1038/s41598-017-18729-5

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. At the early stages of AD development, the soluble β-amyloid (Aβ) induces synaptic dysfunction, perturbs the excitation/inhibition balance of neural circuitries, and in turn alters the normal neural network activity leading to cognitive decline, but the underlying mechanisms are not well established. Here by using whole-cell recordings in acute mouse brain slices, we found that 50 nM Aβ induces hyperexcitability of excitatory pyramidal cells in the cingulate cortex, one of the most vulnerable areas in AD, via depressing inhibitory synaptic transmission. Furthermore, by simultaneously recording multiple cells, we discovered that the inhibitory innervation of pyramidal cells from fast-spiking (FS) interneurons instead of non-FS interneurons is dramatically disrupted by Aβ, and perturbation of the presynaptic inhibitory neurotransmitter gamma-aminobutyric acid (GABA) release underlies this inhibitory input disruption. Finally, we identified the increased dopamine action on dopamine D1 receptor of FS interneurons as a key pathological factor that contributes to GABAergic input perturbation and excitation/inhibition imbalance caused by Aβ. Thus, we conclude that the dopamine receptor 1-dependent disruption of FS GABAergic inhibitory input plays a critical role in Aβ-induced excitation/inhibition imbalance in anterior cingulate cortex.

Highlights

Alzheimer’s disease (AD), the leading cause of dementia in the elderly, is characterized by pathological hallmark of extracellular Amyloid β deposits[1]
To evaluate the effects of Aβ on neuronal excitability, a series of depolarizing currents were injected to elicit action potential (AP) before (Ctrl) and 5–10 mins after 50 nM Aβ administration (Aβ) into perfusing artifical cerebrospinal fluid (ACSF)
The present study demonstrates that 50 nM Aβ leads to hyperexcitability of excitatory pyramidal cells in Anterior cingulate cortex (ACC) through disrupting inhibitory input from FS interneurons

Summary

Introduction

Alzheimer’s disease (AD), the leading cause of dementia in the elderly, is characterized by pathological hallmark of extracellular Amyloid β deposits[1]. Aβ-induced neuronal hyperexcitation and epilepsy are believed to represent the excitotoxic effect which leads to neuronal silencing and cognitive deficits[8,15,16]. By using whole-cell recordings in acute mouse brain slices, we found that 50 nM Aβ leads to hyperexcitability of excitatory pyramidal cells in ACC through depressing inhibitory synaptic innervation from FS but not non-FS interneurons. We identified that the excessive activation of dopamine D1 receptor of FS interneurons leads to Aβ-induced disruption of inhibitory innervation. D1 receptor antagonist SCH23390 can reverse Aβ-induced hyperexcitability of pyramidal cells This suggests that the increased dopamine action on D1 receptor of FS interneurons is the key mechanism in this pathological process

Methods

Results

Conclusion