Hippocalcin-like 4, a neural calcium sensor, has a limited contribution to pain and itch processing.

Christopher G Alvaro,Katherine A Hamel,Allan I Basbaum,Mollie Bernstein,Veronica Craik,João M Braz,Hiroki Yamanaka

doi:10.1371/journal.pone.0226289

Christopher G Alvaro, Katherine A Hamel + Show 5 more

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https://doi.org/10.1371/journal.pone.0226289

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Abstract

Calcium binding proteins are expressed throughout the central and peripheral nervous system and disruption of their activity has major consequences in a wide array of cellular processes, including transmission of nociceptive signals that are processed at the level of the spinal cord. We previously reported that the calcium binding protein, hippocalcin-like 4 (Hpcal4), is heavily expressed in interneurons of the superficial dorsal horn, and that its expression is significantly downregulated in a TR4 mutant mouse model that exhibits major pain and itch deficits due to loss of a subpopulation of excitatory interneurons. That finding suggested that Hpcal4 may be a contributor to the behavioral phenotype of the TR4 mutant mouse. To address this question, here we investigated the behavioral consequences of global deletion of Hpcal4 in a battery of acute and persistent pain and itch tests. Unexpectedly, with the exception of a mild reduction in acute baseline thermal responses, Hpcal4-deficient mice exhibit no major deficits in pain or itch responses, under normal conditions or in the setting of tissue or nerve injury. Taken together, our results indicate that the neural calcium sensor Hpcal4 likely makes a limited contribution to pain and itch processing.

Highlights

The dorsal horn of the spinal cord harbors complex and highly organized neuronal networks through which incoming peripheral sensory information is processed and transmitted to higher centers in the brain
In the course of interrogating the Allen Mouse and Brain Atlas for other genes that are highly expressed in the superficial dorsal horn, and following this with expression studies in the testicular orphan nuclear receptor 4 (TR4) mutant mouse, we identified the neuronal calcium sensory, hippocalcin-like 4 (Hpcal4) as among the most highly expressed genes in the superficial dorsal horn, Most importantly, Hpcal4 expression is greatly reduced in the TR4 mutant mice, which suggested that it predominates in excitatory interneurons
Hpcal4 expression was strongly reduced in the spinal cord of TR4 mutant mice, suggesting that Hpcal4 is expressed by excitatory interneurons and that loss of Hpcal4 activity may have contributed to the behavioral deficits observed in the TR4 mutant mouse

Summary

Introduction

The dorsal horn of the spinal cord harbors complex and highly organized neuronal networks through which incoming peripheral sensory information is processed and transmitted to higher centers in the brain. Major classes of dorsal horn excitatory and inhibitory neurons have been defined according to morphological [1], electrophysiological [2,3,4,5] and neurochemical [6] properties, whether they are engaged by different sensory modalities or respond to multiple stimuli remains the subject of debate. Both specialized and polymodal populations of neurons have been described in the dorsal horn. Mice that no longer express the extracellular matrix protein Reelin have significantly greater heat-, but reduced

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