Fever-like temperatures improve cognitive deficits in the Scn2a autism mouse model via increases in potassium channel...

In some children with autism, fever improves cognition. However, it remains unclear whether the thermal or immune components of fever are responsible for this improvement. Using the Scn2a^+/- autism mouse model, we demonstrate that fever-like temperatures, independent of direct immune activation, normalize cognitive function. In behavioral tests assessing learning of an escape route, Scn2a^+/- juvenile mice at normal body temperature fail to learn, whereas wild-type mice at normal body temperature and Scn2a^+/- mice exposed to infrared light-induced fever, either alone or in combination with immune activation by LPS, exhibit normal learning. Notably, mice with fever alone demonstrated the fastest escape times. Additionally, in novelty recognition tests of textured objects, Scn2a^+/- mice exhibited an increased preference for familiar objects, but fever-like temperatures induced by infrared light exposure or hypothalamic stimulation reversed this abnormality. In the somatosensory cortex, where object texture is perceived, fever-like temperatures reduced excess spiking in Scn2a^+/- pyramidal neurons by increasing potassium channel activation and spike threshold. Chemogenetically reducing spiking at normal temperatures replicated the effects of fever. These findings suggest that thermal fever may offer general cognitive benefits in autism.