Abstract Since the introduction of second-generation antipsychotics, antipsychotics have been increasingly prescribed for children and adolescents, raising concerns about their long-term impact on neurodevelopment. Antipsychotics block dopaminergic and serotonergic receptors, potentially disrupting the maturation of neurocognitive processes, which is a public health concern. Previous studies have reported that adolescent antipsychotic treatment can cause persistent neurocognitive dysfunction in rodents, yet the neurobiological underpinnings remain unknown. To address this, we administered risperidone, a commonly used antipsychotic, to C57BL/6 mice during adolescence (3 to 6 weeks of age) and examined behavioral and neurobiological outcomes nine weeks post-treatment. Risperidone-treated mice exhibited subtle deficits in behavioral correlates of anxiety-like behavior. In vivo, two-photon calcium imaging of cortical neurons revealed a remarkable increase in the amplitude of calcium events with subtle sex-specific changes in the frequency, consistent with increased neuronal excitability. Single-nucleus RNA-sequencing (snRNA-seq) analyses showed widespread reductions in transcripts for voltage-sensitive and inwardly rectifying potassium channels in both pyramidal neurons and interneurons. Additionally, both cell types exhibited reduced Grin2a and Grin2b , as well as scaffolding proteins, indicative of weakened synaptic connectivity between excitatory and inhibitory neurons. Interestingly, we observed sex-dependent differences in the directionality of correlation between certain gene co-expression modules and risperidone treatment. Our results suggest that adolescent risperidone treatment induces lasting transcriptomic and functional changes associated with altered excitatory-inhibitory neuronal interactions that may underline cognitive and behavioral dysregulations.
Alicea-Pauneto et al. (Wed,) studied this question.