NEURONAL PNN DEPLETION IS ASSOCIATED WITH MOLECULAR SYNAPTIC AND BEHAVIORAL ALTERATIONS RELEVANT TO NEURODEGENERATION

Accumulating evidence indicates that genes traditionally classified as housekeeping do not remain stably expressed during aging and may be linked to neurodegenerative conditions. In parallel, dysregulation of RNA processing has emerged as an important contributor to neuronal and synaptic dysfunction. Pnn (Pinin) is a multifunctional RNA splicing regulator originally considered a housekeeping gene; however, its potential involvement in age-related neuronal dysfunction remains unclear. To address this question, we examined the consequences of inducible neuronal Pnn depletion using CaMKII-CreERT2; Pnn^flox/flox mice. Immunofluorescence analyses indicated that neuronal Pnn depletion did not cause overt neuronal loss, whereas longitudinal brain MRI revealed ventricular dilatation and hippocampal atrophy in aged mice. Behavioral assessments revealed age-dependent abnormalities, including increased anxiety-like behavior, impaired social novelty recognition, deficits in spatial learning strategies, and pronounced disruption of innate nesting behavior. Synaptic function was further evaluated by hippocampal long-term potentiation (LTP). While synaptic potentiation was largely preserved at 6 months of age, Pnn-deficient mice exhibited impaired LTP at 12 months, indicating progressive synaptic dysfunction. To relate these functional changes to molecular alterations, we performed Visium spatial gene expression analysis. Transcriptomic profiling identified altered gene expression patterns in the cortex and hippocampus, including reduced expression of synaptic and neuronal maintenance genes (e.g., Syn1, Pdz2, Pxdn) and increased expression of activity- and stress-associated transcripts (e.g., Arc, Pla2g2f). In conclusion, neuronal reduction of a gene originally considered housekeeping is accompanied by molecular, synaptic, and behavioral alterations relevant to neurodegeneration.