Fragile X mental retardation protein (FMRP) and the spinal sensory system - PubMed (original) (raw)
Fragile X mental retardation protein (FMRP) and the spinal sensory system
Theodore J Price et al. Results Probl Cell Differ. 2012.
Abstract
The purpose of this chapter is to discuss the role of the fragile X mental retardation protein (FMRP) in the spinal sensory system and the potential for use of the mouse model of fragile X syndrome to better understand some aspects of the human syndrome as well as advance knowledge in other areas of investigation, such as pain amplification, an important aspect of clinical pain disorders. We describe how the Fmr1 knockout mouse can be used to better understand the role of Fmrp in axons using cultures of sensory neurons and using manipulations to these neurons in vivo. We also discuss the established evidence for a role of Fmrp in nociceptive sensitization and how this evidence relates to an emerging role of translation control as a key process in pain amplification. Finally, we explore opportunities centered on the Fmr1 KO mouse for gaining further insight into the role of translation control in pain amplification and how this model may be used to identify novel therapeutic targets. We conclude that the study of the spinal sensory system in the Fmr1 KO mouse presents several unique prospects for gaining better insight into the human disorder and other clinical issues, such as chronic pain disorders, that affect millions of people worldwide.
Figures
Fig. 4.1
In the peripheral termini of WT sensory neurons, Fmrp facilitates the transport and translational repression of mRNA destined for the axon. Injury, cytokines such as IL-6, and the mGluR1/5 agonist DHPG activate various kinases that increase the excitability of sensory neurons by modulating the activity of TRPV1 and other ion channels. Moreover, activated kinases can induce the initiation of translation [via increased eIF4F complex formation (4 F)], leading to the local synthesis of pronociceptive proteins that enhance and maintain nociceptive sensitization of the primary afferents. In contrast, absence of Fmrp results in the dysregulation of mRNA trafficking and translational repression. Hence, nociceptive inputs that induce prolonged sensitization of the primary afferents may not efficiently induce the local translation of pronociceptive proteins. This results in abrogated responses to injury, IL-6, and DHPG in Fmr1 KO mice
Fig. 4.2
Spinal plasticity in Fmr1 KO mice. (a) Repetitive stimulation of peripheral nociceptors (1) induces windup (an increase in the number of spikes relative to the peripheral input) in the ascending second-order neurons of the spinal cord in WT mice (2). However, in Fmr1 KO mice, a lack of windup, and even winddown (3), was observed in response to the stimulation of peripheral nociceptors (1). (b) Intrathecal injection of mGluR1/5 agonist DHPG (1) may induce LTP in second-order neurons of the spinal cord in WT mice (2), resulting in robust nociceptive behavior. However, intrathecal injection of DHPG fails to induce nociceptive behavior in Fmr1 KO mice (3) compared to that in WT. This lack of nociceptive behavior may reflect a reduction in, or absence of, spinal LTP in Fmr1 KO mice
References
- Adwanikar H, Karim F, Gereau RWt. Inflammation persistently enhances nocifensive behaviors mediated by spinal group I mGluRs through sustained ERK activation. Pain. 2004;111:125–135. - PubMed
- Antar LN, Li C, Zhang H, Carroll RC, Bassell GJ. Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses. Mol Cell Neurosci. 2006;32(1–2):37–48. - PubMed
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