Developmental window of vulnerability to methylphenidate: Selective reduction of prelimbic PV+ interneurons impairs adult attention

Abstract Adolescence is a critical period for the maturation of the medial prefrontal cortex (mPFC), particularly involving the reorganization of the GABAergic network mediated by parvalbumin-expressing (PV+) interneurons. Methylphenidate (MPH), the most commonly prescribed treatment for attention-deficit/hyperactivity disorder (ADHD), is often administered over prolonged periods starting in childhood. However, sustained dopaminergic stimulation during adolescence may interfere with mPFC development by altering dopamine-dependent excitability of PV+ interneurons. In this study, we investigated whether chronic MPH exposure during adolescence affects the acquisition of PV+ interneurons and whether such alterations in GABAergic activity lead to long-lasting impairments in mPFC-dependent functions such as sustained attention. Male and female Wistar rats received 5 mg/kg MPH (a therapeutically relevant dose) for 20 days, beginning in early (PD35–55), middle (PD42–62), or late adolescence (PD49–69). From PD100 onward, animals were tested on a sustained attention task requiring lever presses in response to signal (hit) or non-signal (correct rejection, CR) trials. Once baseline performance reached >75% correct, stimulus durations were reduced to 500 ms, 100 ms, and 25 ms to increase attentional demand. Our results revealed a selective reduction in PV+ interneuron density in the prelimbic, but not infralimbic, cortex—predominantly in animals exposed to MPH during PD49–69. This reduction was associated with persistent deficits in attentional performance in adulthood. These findings highlight the critical role of PV+ interneurons in attentional processes and identify late adolescence as a window of heightened vulnerability during mPFC maturation.