Effects of attenuated TrkB signaling on the medial prefrontal cortex during early brain development: A comparative study using the maternal separation model

Early life stress (ELS) is known to cause long-lasting social and cognitive deficits, but the underlying mechanisms remain unclear. We previously reported that maternal separation (MS), a widely used ELS model, induces transient downregulation of brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (mPFC) during early postnatal development. In this study, we investigated whether this transient suppression of BDNF-TrkB signaling contributes to the reduction in inhibitory neurons and behavioral alterations observed in the MS model. We first confirmed that a single administration of ANA-12, a TrkB antagonist, at postnatal day (PD) 7 suppressed TrkB phosphorylation and downstream signaling in Sprague-Dawley rats. Using this dosage, repeated ANA-12 administration from PD 7–14 decreased the number of inhibitory neurons, particularly parvalbumin-positive interneurons, in adolescence (PD 35), which resembled the changes observed in the MS model. However, these reductions returned to control levels by young adulthood (8 weeks). Behaviorally, ANA-12 treatment impaired working memory in the Y-maze but did not induce social deficits in the modified three-chamber test (3-CST). Furthermore, neural activity during the 3-CST was comparable to that of controls. These findings suggest that early TrkB signaling disruption partially mediates the MS-induced reduction in inhibitory neurons and subsequent cognitive impairment. However, this disruption alone is insufficient to produce persistent social abnormalities. Our findings highlight the complexity of ELS effects and indicate that persistent neural and behavioral alterations likely involve additional mechanisms beyond early TrkB signaling disruption.