Aging alters signaling properties in the mouse spinal dorsal horn

Abstract

A well-recognized relationship exists between aging and increased susceptibility to chronic pain conditions, underpinning the view that pain signaling pathways differ in aged individuals. Yet despite the higher prevalence of altered pain states among the elderly, the majority of preclinical work studying mechanisms of aberrant sensory processing are conducted in juvenile or young adult animals. This mismatch is especially true for electrophysiological studies where patch clamp recordings from aged tissue are generally viewed as particularly challenging. In this study, we have undertaken an electrophysiological characterization of spinal dorsal horn neurons in young adult (3–4 months) and aged (28–32 months) mice. We show that patch clamp data can be routinely acquired in spinal cord slices prepared from aged animals and that the excitability properties of aged dorsal horn neurons differ from recordings in tissue prepared from young animals. Specifically, aged dorsal horn neurons more readily exhibit repetitive action potential discharge, indicative of a more excitable phenotype. This observation was accompanied by a decrease in the amplitude and charge of spontaneous excitatory synaptic input to dorsal horn neurons and an increase in the contribution of GABAergic signaling to spontaneous inhibitory synaptic input in aged recordings. While the functional significance of these altered circuit properties remains to be determined, future work should seek to assess whether such features may render the aged dorsal horn more susceptible to aberrant injury or disease-induced signaling and contribute to increased pain in the elderly.

Transgenic Cross-Referencing of Inhibitory and Excitatory Interneuron Populations to Dissect Neuronal Heterogeneity in the Dorsal Horn

“…This is on the basis of work from our group showing significant alterations in the electrophysiological properties of DH neurons that occur very early in postnatal development-either side of a critical developmental period from P6 to P10 (Walsh et al, 2009). In other work, we have shown there are subtle but significant changes in excitability, excitatory drive, and GABA signaling between young adulthood (3-4 months) and advanced age (28-32 months; Mayhew et al, 2019). Taken together, this supports the view our comparisons are unlikely to be influenced by animal age.…”

Age-related gene expression changes in lumbar spinal cord: Implications for neuropathic pain

“…Finally, the expression of some of the genes we assessed did not show any age-related change in our analysis, including neuroinflammatory and glial related proteins, and the majority of synaptic proteins. This was surprising for the dorsal spinal cord, as our previous work has identified alterations in synaptic function in these circuits with age 17 that predict altered gene expression. This discrepancy could be explained by incomplete translation of gene expression through to protein as suggested above.…”

“…Specifically, DH neurons exhibit a more excitable phenotype along with decreased spontaneous excitatory synaptic input, and an increased contribution of GABAergic signalling to inhibition. 17 While the ultimate outcome of these combined changes for sensory processing under normal and pathological conditions remains to be determined, collectively they confirm that the excitability and signalling in the aged dorsal horn differs from its younger counterpart.…”

Chronic Pain in the Elderly: Mechanisms and Perspectives

“…Collectively, these results imply that age-related changes of PAG networks are implicated in defective pain control circuits in elderly. An interesting set of evidence demonstrated that dorsal horn neurons obtained from old mice exhibited faster action potential discharges, with a reduction of excitatory inputs allied to an increased GABAergic inhibitory signaling, in comparison with the younger ones, according to evaluation by patch clamp electrophysiology ( Mayhew et al, 2019 ). The authors suggested that aged spinal neurons might be more susceptible to injuries, helping to explain the altered pain transmission in the elderly.…”