The regulation of pre-mRNA alternative splicing in neurons is considered to be associated with neurodegeneration disease. In the present study, we applied an inducible neuron-specific gene depletion mouse model to determine whether the expression of Pnn, a mRNA splicing regulator, is involved in the induction of neurodegeneration. Six-weeks old male mice carrying CaMKII-CreERT2 gene cassette and Pnnflox/flox allele were injected with tamoxifen to induce the disruption of Pnn gene structure. In addition to histopathological and biochemical examination, brain MRI analysis and the observation on behavior alteration were also performed on mice with neuronal Pnn depletion. Locomotor activity measurement showed that the travel distance, ratio of moving/resting, central time, and central distance in neuronal Pnn-depleted mice were all higher than that in wild type mice since three months after induction of Pnn gene disruption. Moreover, the decrease in gripping force was observed in mice with neuronal Pnn depletion. MRI analysis further demonstrated that loss of Pnn in neurons leads to cerebral ventricular dilatation and hippocampal atrophy in 10-month-old mice. Mass spectrometry-based immuno-precipitation proteomics indicated the interaction between Pnn and frontotemporal dementia (FTD)-associated proteins, including TDP-43, FUS, and hnRNPA1. It is worth noting that both immunofluorescent stainings and Western blottings demonstrated the up-regulation of FTD-associated proteins in hippocampus and cerebral cortex of mice with neuronal Pnn depletion. However, the transcriptional level of genes involved in FTD were not altered by Pnn depletion. In conclusion, loss of Pnn in neurons leads to behavioral alteration in mice with regulating protein expression of genes involved in FTD, implying the involvement of Pnn deficiency in neurodegeneration. This research was supported by Chang Gung Medical Research Program Grant (Grant number: CMRPG 8N0341-2). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.