Chronic BDNF simultaneously inhibits and unmasks superficial dorsal horn neuronal activity

Sascha R. A. Alles,Peter A. Smith,Van B. Lu,Ryan M. Cassidy,Max A. Odem

doi:10.1038/s41598-021-81269-6

Abstract

Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. However, the mechanisms of BDNF action on specific neuronal populations in the spinal superficial dorsal horn (SDH) requires further study. We used chronic BDNF treatment (200 ng/ml, 5–6 days) of defined-medium, serum-free spinal organotypic cultures to study intracellular calcium ([Ca2+]i) fluctuations. A detailed quantitative analysis of these fluctuations using the Frequency-independent biological signal identification (FIBSI) program revealed that BDNF simultaneously depressed activity in some SDH neurons while it unmasked a particular subpopulation of ‘silent’ neurons causing them to become spontaneously active. Blockade of gap junctions disinhibited a subpopulation of SDH neurons and reduced BDNF-induced synchrony in BDNF-treated cultures. BDNF reduced neuronal excitability assessed by measuring spontaneous excitatory postsynaptic currents. This was similar to the depressive effect of BDNF on the [Ca2+]i fluctuations. This study reveals novel regulatory mechanisms of SDH neuronal excitability in response to BDNF.

Highlights

Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain
We investigated the role of gap junctions in mediating the [Ca2+]i fluctuations; application of the gap junction blocker octanol to chronic BDNF-treated neurons revealed a subpopulation of neurons that generate low-frequency, large [Ca2+]i fluctuations
We used Frequency-independent biological signal identification (FIBSI) to reanalyze a previous dataset of spontaneous excitatory postsynaptic current recordings from BDNF-treated dorsal horn neurons in order to qualitatively compare the effects of BDNF on the sEPSCs and [Ca2+]i fluctuations in superficial dorsal horn (SDH) neurons

Summary

Introduction

Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. Seven or more days of sciatic nerve injury promote an enduring increase in the excitability of first order primary afferent n eurons[5,6,7,8] These become chronically active and release a variety of mediators (cytokines, chemokines, neuropeptides, ATP and growth factors) that predispose spinal microglia to a more ‘activated’ state[9,10,11,12,13,14]. These in turn, release further mediators, including brain derived neurotrophic factor (BDNF) that promote a slowly developing, but persistent increase in excitability of second order neurons in the spinal dorsal horn This ‘central sensitization’ is thought to be responsible for the allodynia, hyperalgesia, spontaneous pain and causalgia that characterize neuropathic pain[3, 15]. This study reveals novel mechanisms of BDNF regulation of dorsal horn excitability, which has implications for the study of chronic neuropathic pain physiology

Objectives

Methods

Results

Conclusion