lncRNA ADEPTR loss-of-function elicits sex-specific behavioral and spine deficits.

Activity-dependent neuronal changes are critical for learning and memory, but the role of long noncoding RNAs (lncRNAs) in these processes is under active investigation. In this study we investigated ADEPTR, a dendritically localized, cAMP-modulated lncRNA essential for synapse morphology. Using two mouse models-one with ADEPTR deletion (L-ADEPTR) and another lacking its protein interaction domain (S-ADEPTR)-we examined sex-specific effects on behavior and neuronal architecture. Behavioral tests showed reduced anxiety in S-ADEPTR adult male mice, with no learning or memory deficits in either model. Neuronal cultures and brain samples from various developmental stages revealed morphological impairments in both sexes. Notably, L-ADEPTR female mice had fewer thin spines in the hippocampal CA1 region at postnatal day 42. Despite these structural deficits, increased expression of plasticity-related genes BDNF and cFOS in the cortex and hippocampus suggests compensatory mechanisms preserve cognitive function. These findings highlight a sex-specific role for ADEPTR in regulating neuronal structure and anxiety-related behaviors.