P02.17.B MANIPULATING GABAERGIC MECHANISMS TO DELAY GLIOMA INVASION IN PERITUMORAL MICROENVIRONMENT

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Abstract BACKGROUND The interaction between tumor cells and the main components of the tumor microenvironment (TME) seems to guide the progression of glioma. Several recent studies have highlighted that the synaptic activity of pyramidal neurons potently drives Glioblastoma (GB) proliferation. However, the role played by other neuronal cell types is still poorly understood. Based on our previous findings showing that the optogenetic stimulation of parvalbuminergic (PV)-inhibitory interneurons negatively regulates glioma progression, here we tested whether a chemogenetic manipulation of peritumoral PV-interneurons could influence GB growth. MATERIAL AND METHODS To address this issue, AAV-hSyn-DIO-hM4D(Gi)-mCherry or AAV-hSyn-DIO-hM4D(Gq)-mCherry were injected in the motor cortex bilaterally with respect to the GL261 injection site in PV-Cre mice. In order to manipulate PV-interneurons activity, animals will be randomized to receive CNO or vehicle intraperitoneally twice a day from day 12 (i.e., the glioma symptomatic stage) to day 22 (i.e., the glioma late stage) post tumor induction. As readouts, we: i) evaluated the tumor volume using Magnetic Resonance Imaging (MRI), ii) performed a longitudinal monitoring of motor capabilities using specific motor tests (i.e., Grip Strength and Grid walk), iii) assessed the survival, iv) determined the GB proliferation index of glioma-bearing mice after different treatments. RESULTS We found that the PV-interneurons inactivation resulted in worsening motor performances with respect to the vehicle mice. Despite that, no difference was observed in animal median survival or tumor volume among the two groups. However, MRI data showed a very significative reduction in the tumor volume at 28 days after glioma induction in PV-activated glioma bearing mice (p=0,004). In addition, PV-activation exert a slight effect on the maximum survival of CNO-treated glioma bearing mice with respect to the vehicle mice (39 vs 32 days). CONCLUSION Since there is no cure for GB, it is essential to find new and effective therapeutic approaches to improve the quality of life and to extend the life expectancy in patients. These data suggest that the inhibitory circuitry in the tumor-adjacent zone could delay GB growth, protecting peritumoral tissue from GB proliferation.

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