Showing papers by "Michael W. Salter published in 2017"

Microglia emerge as central players in brain disease.

Abstract: There has been an explosion of new findings recently giving us insights into the involvement of microglia in central nervous system (CNS) disorders. A host of new molecular tools and mouse models of disease are increasingly implicating this enigmatic type of nervous system cell as a key player in conditions ranging from neurodevelopmental disorders such as autism to neurodegenerative disorders such as Alzheimer's disease and chronic pain. Contemporaneously, diverse roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding learning-associated plasticity. Understanding the physiological functions of these cells is crucial to determining their roles in disease. Here we focus on recent developments in our rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS.

Molecules in pain and sex: a developing story.

Abstract: Microglia are dynamic immune cells with diverse roles in maintaining homeostasis of the central nervous system. Dysregulation of microglia has been critically implicated in the genesis of neuropathic pain. Peripheral nerve injury, a common cause of neuropathic pain, engages microglia-neuronal signalling which causes disinhibition and facilitated excitation of spinal nociceptive pathways. However, recent literature indicates that the role of microglia in neuropathic pain is sexually dimorphic, and that female pain processing appears to be independent of microglia, depending rather on T cells. Despite this sex difference, pain signalling in the spinal cord converges downstream of microglia, as NMDAR-mediated facilitated excitation in pain transmitting neurons is consistent between males and females. Determining whether pain signalling is sexually dimorphic in humans and, further, addressing the sex bias in pain research will increase the translational relevance of preclinical findings and advance our understanding of chronic pain in women.

An evolutionary switch in ND2 enables Src kinase regulation of NMDA receptors

Abstract: The non-receptor tyrosine kinase Src is a key signalling hub for upregulating the function of N-methyl D-aspartate receptors (NMDARs) Src is anchored within the NMDAR complex via NADH dehydrogenase subunit 2 (ND2), a mitochondrially encoded adaptor protein The interacting regions between Src and ND2 have been broadly identified, but the interaction between ND2 and the NMDAR has remained elusive Here we generate a homology model of ND2 and dock it onto the NMDAR via the transmembrane domain of GluN1 This interaction is enabled by the evolutionary loss of three helices in bilaterian ND2 proteins compared to their ancestral homologues We experimentally validate our model and demonstrate that blocking this interaction with an ND2 fragment identified in our experimental studies prevents Src-mediated upregulation of NMDAR currents in neurons Our findings establish the mode of interaction between an NMDAR accessory protein with one of the core subunits of the receptor

Advancing research and clinical care in the management of neuropathic pain after spinal cord injury: Key findings from a Canadian summit

Abstract: Background: Optimal management of neuropathic pain (NP) is essential to enhancing health-related quality of life for individuals living with spinal cord injury (SCI). A key strategic priority for the Ontario Neurotrauma Foundation (ONF) and Rick Hansen Institute (RHI) is optimizing NP management after SCI.Aims: A National Canadian Summit, sponsored by ONF and RHI, was held to develop a strategic plan to improve NP management after SCI.Methods: In a one-day meeting held in Toronto, Ontario, a multidisciplinary panel of 18 Canadian stakeholders utilized a consensus workshop methodology to (1) describe the current state of the field, (2) create a long-term vision, and (3) identify steps for moving into action.Results: A review of the current state of the field identified strengths including rigourously developed evidence syntheses and practice landscape documentation. Identified gaps included limited evidence on NP hindering recommendation development in evidence syntheses, absence of a national stra...

VIP cortical conductors set the tone for chronic pain

Abstract: Loss of inhibition in a circuit in the primary somatosensory cortex that controls the activity of layer 5 neurons drives pain hypersensitivity. Restoring this inhibition resets the inhibitory–excitatory balance, producing analgesia.