Recovery of hippocampal functions and modulation of muscarinic response by electroacupuncture in young diabetic rats

Marzia Soligo,Virginia Protto,Luigi Manni,Erica Berretta,Sonia Piccinin,Maria Egle De Stefano,Robert Nisticò,Laura Petrosini,Francesca Gelfo,Fulvio Florenzano

doi:10.1038/s41598-017-08556-z

Abstract

The muscarinic receptor response to acetylcholine regulates the hippocampal-related learning, memory, neural plasticity and the production and processing of the pro-nerve growth factor (proNGF) by hippocampal cells. The development and progression of diabetes generate a mild cognitive impairment reducing the functions of the septo-hippocampal cholinergic circuitry, depressing neural plasticity and inducing proNGF accumulation in the brain. Here we demonstrate, in a rat model of early type-1 diabetes, that a physical therapy, the electroacupuncture, counteracts the diabetes-induced deleterious effects on hippocampal physiology by ameliorating hippocampal-related memory functions; recovering the impaired long-term potentiation at the dentate gyrus (DG-LTP) and the lowered expression of the vesicular glutamate transporter 1; normalizing the activity-dependent release of proNGF in diabetic rat hippocampus. Electroacupuncture exerted its therapeutic effects by regulating the expression and activity of M1- and M2-acetylcholine muscarinic receptors subtypes in the dentate gyrus of hippocampus. Our results suggest that a physical therapy based on repetitive sensory stimulation could promote hippocampal neural activity, neuronal metabolism and functions, and conceivably improve the diabetes-induced cognitive impairment. Our data can support the setup of therapeutic protocols based on a better integration between physical therapies and pharmacology for the cure of diabetes-associated neurodegeneration and possibly for Alzheimer’s disease.

Highlights

Dysfunctions in hippocampus-related behaviour and neural plasticity characterize both Alzheimer’s disease and diabetic encephalopathy[1,2,3] that share common hallmarks, such as accumulation of beta-amyloid, of hyper-phosphorylated tau[4, 5] and of the pro-nerve growth factor in the brain[6, 7]
We studied whether functional changes in the dentate gyrus (DG) excitatory transmission were associated with alterations in tissue distribution of a major marker of glutamatergic transmission, the vesicular glutamate transporter-1
Since pro-nerve growth factor (proNGF) release is under cholinergic control, we explored the role of the two main muscarinic acetylcholine (ACh) receptors expressed in the hippocampus, M1AChR and M2AChR, after diabetes induction and/or electroacupuncture

Summary

Introduction

Dysfunctions in hippocampus-related behaviour and neural plasticity characterize both Alzheimer’s disease and diabetic encephalopathy[1,2,3] that share common hallmarks, such as accumulation of beta-amyloid, of hyper-phosphorylated tau[4, 5] and of the pro-nerve growth factor (proNGF) in the brain[6, 7]. The BFCNs activity modulates hippocampal plasticity and regulates the production, secretion and processing of proNGF by hippocampal cells[9, 10] providing a sort of “on demand” supply of the pro-neurotrophin. This in turn regulates remote BFCN metabolism[11] and directly influences hippocampal neurons survival[12, 13], functions and plasticity[14]. Our work aimed at studying the impact of early type-1 diabetes and electroacupuncture on activity-regulated hippocampal functions, namely the generation of LTP at dentate gyrus (DG-LTP) and the release and extracellular processing of proNGF. We explored the mechanistic hypothesis that electroacupuncture corrects the diabetes-induced dysregulation in DG-LTP and proNGF release by acting on the hippocampal muscarinic responsivity

Methods

Results

Conclusion