Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons

Nolan M. Dvorak, Paul A. Wadsworth, Guillermo Aquino-Miranda, Pingyuan Wang, Douglas S. Engelke, Jingheng Zhou, Nghi Nguyen, Aditya K. Singh, Giuseppe Aceto, Zahra Haghighijoo, Isabella I. Smith, Nana Goode, Mingxiang Zhou, Yosef Avchalumov, Evan P. Troendle, Cynthia M. Tapia, Haiying Chen, Reid T. Powell, Timothy J. Baumgartner, Jully Singh, Leandra Koff, Jessica Re, Ann E. Wadsworth, Mate Marosi, Marc R. Azar, Kristina Elias, Paul Lehmann, Yorkiris M. Mármol Contreras, Poonam Shah, Hector Gutierrez, Thomas A. Green, Martin B. Ulmschneider, Marcello D’Ascenzo, Clifford Stephan, Guohong Cui, Fabricio H. Monte, Jia Zhou and Fernanda Laezza ()
Additional contact information
Nolan M. Dvorak: University of Texas Medical Branch
Paul A. Wadsworth: University of Texas Medical Branch
Guillermo Aquino-Miranda: University of Texas Health Science Center
Pingyuan Wang: University of Texas Medical Branch
Douglas S. Engelke: University of Texas Health Science Center
Jingheng Zhou: Research Triangle Park
Nghi Nguyen: Texas A&M Health Science Center
Aditya K. Singh: University of Texas Medical Branch
Giuseppe Aceto: Università Cattolica del Sacro Cuore
Zahra Haghighijoo: University of Texas Medical Branch
Isabella I. Smith: University of Texas Health Science Center
Nana Goode: University of Texas Medical Branch
Mingxiang Zhou: University of Texas Medical Branch
Yosef Avchalumov: University of Texas Medical Branch
Evan P. Troendle: King’s College London 7 Trinity Street
Cynthia M. Tapia: University of Texas Medical Branch
Haiying Chen: University of Texas Medical Branch
Reid T. Powell: Texas A&M Health Science Center
Timothy J. Baumgartner: University of Texas Medical Branch
Jully Singh: University of Texas Medical Branch
Leandra Koff: University of Texas Medical Branch
Jessica Re: University of Texas Medical Branch
Ann E. Wadsworth: University of Texas Medical Branch
Mate Marosi: University of Texas Medical Branch
Marc R. Azar: Suite 212
Kristina Elias: Suite 212
Paul Lehmann: University of Texas Medical Branch
Yorkiris M. Mármol Contreras: University of Texas Medical Branch
Poonam Shah: University of Texas Medical Branch
Hector Gutierrez: University of Texas Medical Branch
Thomas A. Green: University of Texas Medical Branch
Martin B. Ulmschneider: King’s College London 7 Trinity Street
Marcello D’Ascenzo: Università Cattolica del Sacro Cuore
Clifford Stephan: Texas A&M Health Science Center
Guohong Cui: Research Triangle Park
Fabricio H. Monte: University of Texas Health Science Center
Jia Zhou: University of Texas Medical Branch
Fernanda Laezza: University of Texas Medical Branch

Nature Communications, 2025, vol. 16, issue 1, 1-27

Abstract: Abstract Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14R117, a critical residue located within a druggable pocket at the FGF14/Nav1.6 PPI interface. We found that 1028 modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Nav1.6 channel. Consistent with the compound’s effects on Nav1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons.

Date: 2025
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DOI: 10.1038/s41467-024-55554-7

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