A functional
nerve growth factor NGF-
Tropomyosin Receptor
kinase A (TrkA) system is an essential requisite for the generation and maintenance of long-lasting thermal and
mechanical hyperalgesia in adult mammals. Indeed, mutations in the gene encoding for TrkA are responsible for a rare condition, named
Hereditary Sensory and Autonomic Neuropathy type IV (
HSAN IV), characterized by the loss of response to noxious stimuli,
anhidrosis and
cognitive impairment. However, to date, there is no available mouse model to properly understand how the
NGF-TrkA system can lead to pathological phenotypes that are distinctive of
HSAN IV. Here, we report the generation of a knock-in mouse line carrying the
HSAN IV TrkAR649W mutation. First, by in vitro biochemical and biophysical analyses, we show that the pathological R649W mutation leads to
kinase-inactive TrkA also affecting its membrane dynamics and trafficking. In agreement with the
HSAN IV human phenotype, TrkAR649W/m mice display a lower response to thermal and chemical noxious stimuli, correlating with reduced skin innervation, in addition to decreased sweating in comparison to TrkAh/m controls. Moreover, the R649W mutation decreases anxiety-like behavior and compromises cognitive abilities, by impairing spatial-working and social memory. Our results further uncover unexplored roles of TrkA in thermoregulation and sociability. In addition to accurately recapitulating the clinical manifestations of
HSAN IV patients, our findings contribute to clarifying the involvement of the
NGF-TrkA system in
pain sensation.