Induction of a reactive state in perineuronal satellite glial cells akin to that produced by nerve injury is linked to the level of p75NTR expression in adult sensory neurons

Abstract

Satellite glial cells (SGCs) surrounding primary sensory neurons are similar to astrocytes of the central nervous system in that they buffer the extracellular environment via potassium and calcium channels and express the intermediate filament glial fibrillary acidic protein (GFAP). Peripheral nerve injury induces a reactive state in SGCs that includes SGC proliferation, increased SGC/SGC coupling via gap junctions, decreased inward rectifying potassium channel 4.1 (Kir 4.1) expression and increased expression of GFAP and the common neurotrophin receptor, p75NTR. In contrast, neuronal p75NTR expression, normally detected in ∼80% of adult rat sensory neurons, decreases in response to peripheral axotomy. Given the differential regulation of p75NTR expression in neurons versus SGCs with injury, we hypothesized that reduced signaling via neuronal p75NTR contributes to the induction of a reactive state in SGCs. We found that reducing neuronal p75NTR protein expression in uninjured sensory neurons by intrathecal subarachnoid infusion of p75NTR-selective anti-sense oligodeoxynucleotides for one week was sufficient to induce a "reactive-like" state in the perineuronal SGCs akin to that normally observed following peripheral nerve injury. This reactive state included significantly increased SGC p75NTR, GFAP and gap junction protein connexin-43 protein expression, increased numbers of SGCs surrounding individual sensory neurons and decreased SGC Kir 4.1 channel expression. Collectively, this supports the tenet that reductions in target-derived trophic support leading to, or as a consequence of, reduced neuronal p75NTR expression plays a critical role in switching the SGC to a reactive state.

Changes in the transcriptional fingerprint of satellite glial cells following peripheral nerve injury

“…However, considering our results here on macrophages assuming SGC‐like localization, it may also be possible that IL6, IL6R or TNFα were detected in peri‐neuronal macrophages. The problem may be compounded by the widespread use of GFAP as a marker for activated SGCs in a variety of animal models of nerve injury (Blum et al, ; Gunjigake et al, ; Hanani et al, ; Nadeau et al, ; Ohara et al, ; Ohtori et al, ; Woodham et al, ; Xu et al, ). Surprisingly, we did not find mRNA expression of GFAP in either naïve SGCs, sham SGCs or injured SGCs (Table and File S1), and we could not detect any basal or elevated GFAP levels by IHC (data not shown).…”

“…At the structural level, SGCs appear to change morphology (Pannese, ) and to undergo proliferation (Donegan, Kernisant, Cua, Jasmin, & Ohara, ; Friede & Johnstone, ; Lu & Richardson, ; Shinder et al, ; Vit, Jasmin, Bhargava, & Ohara, ), as well as to increase inter‐SGC coupling via gap junctions (Cherkas et al, ; Hanani, Huang, Cherkas, Ledda, & Pannese, ; Huang, Cherkas, Rosenthal, & Hanani, ; Pannese, Ledda, Cherkas, Huang, & Hanani, ; Spray et al, ; Suadicani et al, ). Upregulation of glial fibrillary acidic protein (GFAP) is also described (Liu et al, ; Vit et al, ; Woodham, Anderson, Nadim, & Turmaine, ), which is often used as a marker for activated SGCs (Blum, Procacci, Conte, Sartori, & Hanani, ; Gunjigake, Goto, Nakao, Kobayashi, & Yamaguchi, ; Hanani, Blum, Liu, Peng, & Liang, ; Nadeau, Wilson‐Gerwing, & Verge, ; Ohara et al, ; Ohtori, Takahashi, Moriya, & Myers, ). Furthermore, a decreased expression of the K + channel Kir4.1 is believed to promote hyperexcitability and sensitization of peripheral neurons, which ultimately contributes to neuropathic pain (Takeda, Takahashi, Nasu, & Matsumoto, ; Vit et al, ; Vit, Ohara, Bhargava, Kelley, & Jasmin, ).…”

Satellite glial cells represent a population of developmentally arrested Schwann cells

“…SGCs have been ascribed to have functions similar to those of astrocytes in the CNS, in that they control the microenvironment around the neural soma and hence can modulate the activity of these neurons through complex SGC, neuronal soma cross communication (reviewed in Costa & Moreira Neto, ; Huang, Gu, & Chen, ). In addition, they exhibit an ‘activated’ state in response to neural injury, and propagate that state to other SGCs through calcium signaling (Donegan, Kernisant, Cua, Jasmin, & Ohara, ; Nadeau, Wilson‐Gerwing, & Verge, ; Suadicani et al, ). This phenomenon results in the recruitment of other neurons to the injury response, hence, implicating SGCs in the development of chronic pain (Dublin & Hanani, ; Suadicani et al, ).…”

“…In addition, they exhibit an 'activated' state in response to neural injury, and propagate that state to other SGCs through calcium signaling (Donegan, Kernisant, Cua, Jasmin, & Ohara, 2013;Nadeau, Wilson-Gerwing, & Verge, 2014;Suadicani et al, 2010). This phenomenon results in the recruitment of other neurons to the injury response, hence, implicating SGCs in the development of chronic pain (Dublin & Hanani, 2007;Suadicani et al, 2010).…”

P2Y2 receptor antagonists as anti‐allodynic agents in acute and sub‐chronic trigeminal sensitization: Role of satellite glial cells

“…“Classical” analgesic drugs mostly target neurons, which become sensitized under TG painful conditions (Chen et al, ). In sensory ganglia, neuronal bodies are surrounded and wrapped by satellite glial cells (SGCs; Pannese, ), and accumulating data highlight their fundamental role in modulating neuronal firing, and, ultimately, painful sensations (Huang et al, ; Ji et al, ), thanks to their ability to react to pathophysiological changes (Donegan et al, ; Nadeau et al, ; Schaeffer et al, ). Thus, understanding the complex molecular network controlling neuron‐to‐SGC communication might unveil new targets to be exploited to more efficiently control neuronal sensitization.…”