Probing brain circuit and behavior with protein:protein interaction modulators

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ABSTRACT Psychiatric diseases are complex brain disorders associated with maladaptive plasticity of the brain circuit for which we lack predictive preclinical measures of clinical efficacy. To fill this gap, we need to use molecular knowledge to inform development of novel probes in order to interrogate the mechanisms that underlie circuit deficits in these disorders and drive advanced therapeutic design. Protein-protein interactions (PPI) within ion channel complexes fine-tune neuronal excitability and are emerging as links to the biology of psychiatric disorders. Their highly specific and flexible interfaces make protein-channel interactions ideal targets for probe development. Such molecular probes would provide the neuropharmacology community with optimal research tools to parse out brain disease complexities and enable more effective drug design. We have identified the PPI between the voltage-gated Na+ (Nav) Nav1.6 channel and its accessory regulator protein, fibroblast growth factor 14 (FGF14) as a functionally relevant regulator of excitability of medium spiny neurons (MSN) in the nucleus accumbens (NAc); a central component of the mesocorticolimbic circuit whose dysfunction has been associated with a wide spectrum of neuropsychiatric disorders. Through a bioluminescence-based high-throughput screen (HTS) and a round of chemical optimization we have identified the new brain permeable probe 1028 that modulates FGF14:Nav1.6 channel complex formation and increases Nav1.6 channel availability and MSN firing. When systemically administrated, 1028 increases accumbal neuron firing and promotes hedonic states in situations lacking motivation, suggesting the compound can modulate reward-related behaviors within the mesocorticolimbic circuit. Here, we are proposing to further optimize 1028 for in vivo use by improving its potency and metabolic stability and determine its mechanism of action at the molecular (Aim 1), cellular (Aim 2), circuital, and behavioral levels (Aim 3). Outcomes of this proposed research will generate the first-in-class brain-permeant chemical probes to interrogate the reward circuit, providing the foundation for pre-therapeutic development of a new class of PPI-based leads for a broad spectrum of psychiatric disorders.