CNSC-65. THE EFFECT OF PERITUMORAL NEURONAL MTOR INHIBITION ON PERITUMORAL GABAERGIC TONE, PERITUMORAL EXCITABILITY AND NEURON-DRIVEN GLIOMA GROWTH

Abstract Tumor-induced decreases in inhibitory GABAergic tone contribute to cortical excitability, which may clinically manifest as seizures and interictal epileptiform discharges (IEDs). Tumor-associated epileptic events are often refractory to anticonvulsants and negatively impact patient quality of life. Recent evidence suggests that peritumoral neuronal hyperactivity can drive glioma growth and progression. Thus, novel therapeutic strategies are urgently needed to address both glioma growth and cortical excitability. We previously reported that peritumoral GABAergic dysfunction underlies tumor-associated seizures and that a dual mTOR inhibitor can restore inhibitory GABAergic tone. Here, we aim to determine if there is a synergistic effect of combining mTOR inhibitors with GABAergic agonists, as this class of anticonvulsants are expected to become more effective with restoration of inhibitory GABAergic tone. We hypothesize that mTOR-mediated increases in inhibitory GABAergic tone combined with GABAergic agonists in vivo will reduce epileptic activity and calcium transients in glioma cells. To do this, we used glioma cells engineered to express the calcium reporter GCaMP6s in combination with transgenic mouse models expressing the calcium reporter jRGECO1a in excitatory neurons. Mice were treated with an mTOR inhibitor, a GABAergic agonist, combination of the two drugs or vehicle. Seizure and IED frequency were assessed using continuous telemetric electrocephalography. Mesoscopic dual-color optical mapping of calcium transients in both cell populations was performed to determine how seizures and IEDs influence tumor cell calcium activity. Preliminary data indicate that combined treatment with mTOR inhibitors and GABAergic agonists yields a greater reduction in both seizure frequency and glioma cell calcium transients compared to either treatment alone. This is the first study to combine mTOR pathway inhibition with GABAergic modulation in a glioma model. Our findings suggest that this multimodal approach can alleviate tumor-associated cortical hyperexcitability while potentially slowing glioma progression, representing a promising strategy to improve patient quality of life and survival.