Regulating Neuronal Hyperexcitability: The Role of Glutamate Transport, Cannabinoids, and Platinum-Based Anti-Cancer Drugs

Our studies consist of three distinct projects addressing the modulation of neuronal hyperexcitability states. Hyperexcitability is linked to many neurological disorders and can occur as a consequence of excitatory/inhibitory imbalance, head trauma, or chemical toxin exposure. In this dissertation, each project uses distinct pharmacological approaches in two models of hyperexcitability. The first study focuses on glutamate dysregulation in the hyper-excitable physiological state called cortical spreading depression (CSD). CSD is implicated in several neurological disorders including stroke, migraine aura, epilepsy, and traumatic brain injury (TBI). Despite the critical link between increased glutamate levels during CSD and following TBI, the role of astrocytic glutamate transporters on CSD properties remain unknown. We revealed that impaired glutamate transport and acute injury profoundly affected the physiological and spatiotemporal properties of CSD and neuronal excitability. Our findings emphasize the importance of glutamate transport and brain injury on CSD characteristics, opening new treatment avenues for CSD and related disorders such as migraine and seizure. Our second study observes the effects of the major non-psychoactive cannabinoid – cannabidiol (CBD) and its acidic precursor – cannabidiolic acid (CBDA) on intrinsic neuron electrophysiological characteristics and on control of neuronal hyperexcitability. This study was motivated by several human reports of the potent anti-epileptic properties of CBD in intractable epilepsies, a void in known mechanisms of actions of CBDA, and a lack of information regarding the effects CBD and CBDA on single neuron and network physiology. We show that CBD and CBDA can control neuronal hyperexcitability in a robust in vitro seizure model. Our findings from this project highlight that CBDA can effectively control neuronal cell properties and seizure-like activity in vitro. The third project examined the neuromodulatory properties of the novel platinum derivative anticancer compounds (RRD4) and oxaliplatin on CA1 pyramidal neurons. Rare cases of chemotherapy-induced seizures during or after administration of platinum- derived agents, like oxaliplatin, are well documented. RRD4 is structurally similar to oxaliplatin, but it contains phosphate groups and showed contrasting effects to RRD4. Oxaliplatin changed intrinsic cell membrane properties, induced hyperexcitability and even caused cell death, while RRD4 only reduced seizure-like hyperexcitability.