Hyperactive Akt-mTOR pathway as a therapeutic target for pain hypersensitivity in Cntnap2-deficient mice

Contactin-associated protein-like 2 (CNTNAP2 or CASPR2) is a neuronal transmembrane protein of the neurexin superfamily that is involved in many neurological diseases, such as autism and pain hypersensitivity. We recently found that Cntnap2^-/- mice showed elevated Akt-mTOR activity in the brain, and suppression of the Akt-mTOR pathway rescued the social deficit in Cntnap2^-/- mice. In this study, we found that the dorsal root ganglion (DRG) from Cntnap2^-/- mice also showed hyperactive Akt-mTOR signaling. Treatment with the Akt inhibitor LY94002 or the mTOR inhibitor rapamycin attenuated pain-related hypersensitivity to noxious mechanical stimuli, heat, and inflammatory substances. Further, suppression of mTOR signaling by rapamycin decreased DRG neuronal hyperexcitability. We further indicated that treatment with the FDA-approved drug metformin normalized the hyperactive Akt-mTOR signaling, and attenuated pain-related hypersensitivity in Cntnap2^-/- mice. Our results thus identified hyperactive Akt-mTOR signaling pathway as a promising therapeutic target for pain-related hypersensitivity in patients with dysfunction of CNTNAP2.