AAV-mediated overexpression of Prdm12 in knee-innervating afferents reduces inflammatory joint pain and neuronal hyperexcitability in female mice

Abstract

Inflammatory joint pain features in numerous musculoskeletal disorders that affect millions globally. The Prdm12 gene encodes a conserved zinc finger transcriptional regulator expressed selectively in the nervous system. In humans, PRDM12 mutations can cause congenital insensitivity to pain (CIP) or midface toddler excoriation syndrome (MiTES). Prdm12 is prominently expressed in developing somatosensory ganglia, where it plays a crucial role in nociceptive neuron development, its expression being maintained in mature C-LTMRs (C-low threshold mechanoreceptors) and nociceptive neurons. Despite enhanced understanding of Prdm12’s role in neuronal excitability and pain behavior, the impact of Prdm12 overexpression in mature nociceptive neurons has not been explored. Here, we conducted intravenous injection of AAV-PHP.S viral vectors encoding Prdm12-GFP (Prdm12-AAV) or GFP alone (Control-AAV), observing no change in thermal or motor behavior. When examining the properties of Prdm12 overexpressing sensory neurons isolated from male mice, we observed an increase in rheobase alongside decreased neuronal responses to capsaicin and ATP, indicating a decrease in TRPV1 and P2X ion channel activity, respectively. We next conducted intraarticular administration of viral constructs in female mice to determine how Prdm12 overexpression in knee-innervating sensory neurons alters their excitability and influences inflammatory joint pain induced by intraarticular administration of complete Freund’s adjuvant (CFA). Prdm12 overexpression in knee-innervating neurons decreased inflammation-induced changes in digging and weight bearing, prevented inflammation-induced neuronal hyperexcitability, and decreased macroscopic voltage-gated ion channel conductance. Our findings illustrate that Prdm12 overexpression strongly modulates neuronal excitability in adult animals, highlighting its importance in pain perception and its potential as an analgesic target. Significance Statement Chronic joint pain is a major cause of disability worldwide, yet effective treatments remain limited. This study identifies the transcriptional regulator Prdm12 as a key modulator of sensory neuron excitability and inflammatory joint pain in adult mice. Using AAV-mediated gene delivery, we show that Prdm12 overexpression in knee-innervating neurons prevents inflammation-induced neuronal hyperexcitability and reduces pain-related behaviors in female mice. These findings extend Prdm12’s known developmental roles into adulthood and reveal its capacity to suppress nociceptive signaling. Our results suggest that targeted overexpression of Prdm12 activity could represent a novel gene-based strategy for treating chronic inflammatory pain conditions.