3-Methyladenine administration alleviates cognitive and memory dysfunction in attention-deficit/hyperactivity disorder by modulating autophagy.

BACKGROUND

Attention-deficit/hyperactivity disorder (ADHD), a highly prevalent neurodevelopmental disorder among children, is directly associated with impairments in cognition and memory. In the nervous system, autophagy is essential for the development of neurons, the formation and remodeling of synapses, and the transmission of neurotransmitters. The 3-methyladenine (3-MA), an autophagy inhibitor, mitigates cognitive and memory impairment in neurological disorders. This study aimed to investigate the potential role of 3-MA in ADHD.

METHODS

An ADHD model was established in offspring mice by intraperitoneal injection of S-ketamine during mid-to-late gestation. Postnatal day 14 offspring received intraperitoneal 3-MA (15 mg/kg/day) or vehicle for 7 consecutive days. To assess behavioral, electrophysiological, and pathological changes in mice, several tests were employed, including the open field test (OFT), novel object recognition (NOR) test, fear conditioning (FC), local field potential recording, western blot, transmission electron microscopy and immunofluorescence assays.

RESULTS

Compared to controls, ADHD model mice exhibited: Increased total distance in OFT, Decreased recognition index in NOR, Reduced context- and cue-related freezing time in FC and Attenuated theta oscillation power in the prefrontal cortex. RNA sequencing revealed significant enrichment of the PI3KC3 pathway and autophagy-related genes. ADHD model mice showed upregulated autophagy-related protein expression, elevated LC3II/I ratio, increased autophagosomes, and accumulated abnormal organelles in the mPFC. TH-positive neurities and PSD95-positive puncta were significantly reduced in the mPFC. 3-MA treatment partially reversed these alterations.

CONCLUSION

Cognitive and memory impairments in the mPFC due to ADHD are correlated with autophagy, and these impairments might be alleviated by 3-MA.