Behavioral and morphological characterization of altered TDP-43 expression in rats via viral-mediated gene transfer method

Aim: This study aimed to investigate changes in behavior and morphology in a rat model with increased TDP-43 expression, a protein implicated in various cellular functions. Methods: The rat model was established using Adeno-Associated Viruses (AAV9), with genes encoding TDP-43 injected into the systemic circulation of postnatal (P) 30-day-old male Sprague-Dawley rats (n=10/group). A control group received physiological saline (n=12). Dose groups were set at 3.2x1012 gc/ml, 1.6x1012 gc/ml, and 0.8x1012 gc/ml. Evaluations included motor behavior, anxiety, cognitive abilities, and social skills, alongside morphological assessments of brain and spinal cord sections. Results: Survival time, body weight, gait analysis, rotarod test results, and performance in the eight-arm radial maze showed no significant differences between groups. However, we noted a dose-dependent regression in the horizontal walking test (p < 0.001). The 3.2 x 1012 gc/ml group exhibited increased time spent in the midfield during social recognition tests (p < 0.05). While brain volumetric measurements and NeuN-positive neuron counts remained unchanged, spinal cord sections exhibited a significant dose-dependent decrease (p < 0.001). Ubiquitin-positive, p-TDP-43 and TDP-43 inclusions were observed in several brain regions. Conclusion: This study provides insights into motor and cognitive impairments linked to TDP-43 overexpression, enhancing our understanding of TDP-43 proteinopathy mechanisms, particularly during its prodromal phase. Keywords: TDP-43 Proteinopathies, Neurodegeneration, Animal models This thesis was supported by TÜSEB (Project No: 32137).