Psychiatric diseases are chronic, devastating disorders thought to arise from maladaptive brain plasticity, and potent and safe pharmacotherapies are in great need. Identifying the mechanistic links that might sustain these aberrant neuroadaptations will advance our understanding of the biology of mental disorders, potentially providing new platforms for medication development. Using an innovative bioluminescence-based molecular screening approach combined with biochemical, electrophysiological, and imaging assays, we provide breakthrough results showing a link between glycogen synthase kinase 3 (GSK3), a critical enzyme found dysfunctional in mood disorders, depression and schizophrenia, and neuronal excitability, which we propose as a potential mechanism underlying dysfunction of neuronal circuitries associated with psychiatric disorders and certain addictive behaviors. Building on previous discoveries demonstrating that fibroblast growth factor 14 (FGF14) is a functionally relevant component of the Nav channelosome that controls neuronal excitability, we present exciting new data showing that the FGF14:Nav channel complex formation is bi-directionally controlled by GSK3 and by the GSK3 constitutive repressor, protein kinase B (Akt), and that GSK3 directly phosphorylates FGF14. Pharmacological inhibition of Akt and GSK increases and prevents, respectively, the FGF14:Nav channel complex formation, whereas inhibition of GSK3 occludes the effect of Akt inhibition. In hippocampal neurons, GSK3 inhibition disperses the FGF14:Nav channel complex from the axonal initial segment (AIS), the site of action potential initiation, impairs intrinsic fring and reduces excitatory synaptic transmission, whereas inhibition of Akt leads to opposite phenotypes. Furthermore, we show that Fpep1, a small interfering peptide modeled upon the FGF14:Nav channel interface, prevents the FGF14:Nav channel complex assembly, providing a tool for minimizing the effect of GSK3 on neuronal excitability in vivo. In this proposal we will employ a combination of bioluminescence-based technology, mass spectrometry, phosphorylation assays, confocal imaging and electrophysiology to determine the molecular mechanism by which GSK3 controls the FGF14:Nav channel complex formation (Aim 1) and promotes targeting of the FGF14:Nav channel complex in neurons (Aim 2) and to evaluate whether GSK3 exerts an effect on excitability and neuroplasticity in cortico-limbic circuits through the FGF14:Nav channel complex that could be reversed by pharmacological or genetic approaches targeting FGF14 (Aim 3). Positive outcomes of this study will provide new insights into the molecular mechanisms of GSK3 in the brain and offer an unprecedented opportunity for new medication development against GSK3-linked psychiatric disorders.

Public Health Relevance

Innovative and integrated approaches are needed to enhance the success of therapeutic interventions against psychiatric disorders. Through a multidisciplinary project including molecular biology, biochemistry mass spectrometry, single cell imaging and electrophysiology in rodent models, we will validate FGF14 as a novel downstream target of GSK3, creating a novel platform for intervention against psychiatric disorders associated with GSK3 dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH095995-01A1
Application #
8373279
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
2012-08-01
Project End
2017-04-30
Budget Start
2012-08-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$382,500
Indirect Cost
$132,500
Name
University of Texas Medical Br Galveston
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
James, T F; Nenov, Miroslav N; Tapia, Cynthia M et al. (2017) Consequences of acute Nav1.1 exposure to deltamethrin. Neurotoxicology 60:150-160
Crofton, Elizabeth J; Nenov, Miroslav N; Zhang, Yafang et al. (2017) Glycogen synthase kinase 3 beta alters anxiety-, depression-, and addiction-related behaviors and neuronal activity in the nucleus accumbens shell. Neuropharmacology 117:49-60
Hsu, Wei-Chun J; Wildburger, Norelle C; Haidacher, Sigmund J et al. (2017) PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease. Exp Neurol 295:1-17
Alshammari, Musaad A; Alshammari, Tahani K; Nenov, Miroslav N et al. (2016) Fibroblast Growth Factor 14 Modulates the Neurogenesis of Granule Neurons in the Adult Dentate Gyrus. Mol Neurobiol 53:7254-7270
Singh, Pankaj; Negi, Pooran; Laezza, Fernanda et al. (2016) Multiscale Analysis of Neurite Orientation and Spatial Organization in Neuronal Images. Neuroinformatics 14:465-77
Ali, Syed R; Singh, Aditya K; Laezza, Fernanda (2016) Identification of Amino Acid Residues in Fibroblast Growth Factor 14 (FGF14) Required for Structure-Function Interactions with Voltage-gated Sodium Channel Nav1.6. J Biol Chem 291:11268-84
Hsu, Wei-Chun J; Scala, Federico; Nenov, Miroslav N et al. (2016) CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability. FASEB J 30:2171-86
Alshammari, T K; Alshammari, M A; Nenov, M N et al. (2016) Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia. Transl Psychiatry 6:e806
Alshammari, Musaad A; Alshammari, Tahani K; Laezza, Fernanda (2016) Improved Methods for Fluorescence Microscopy Detection of Macromolecules at the Axon Initial Segment. Front Cell Neurosci 10:5
Ozcan, Burcin; Negi, Pooran; Laezza, Fernanda et al. (2015) Automated detection of soma location and morphology in neuronal network cultures. PLoS One 10:e0121886

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