| Summary: | Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male <i>Fgf14</i><sup>−/−</sup> mice recapitulate the salient endophenotypes of synaptic dysfunction and behaviors that are associated with schizophrenia (SZ). As the underlying etiology of SZ and its sex-specific onset remain elusive, the <i>Fgf14</i><sup>−/−</sup> model may provide a valuable tool to interrogate pathways related to disease mechanisms. Here, we performed label-free quantitative proteomics to identify enriched pathways in both male and female hippocampi from <i>Fgf14</i><sup>+/+</sup> and <i>Fgf14</i><sup>−/−</sup> mice. We discovered that all of the differentially expressed proteins measured in <i>Fgf14</i><sup>−/−</sup> animals, relative to their same-sex wildtype counterparts, are associated with SZ based on genome-wide association data. In addition, measured changes in the proteome were predominantly sex-specific, with the male <i>Fgf14</i><sup>−/−</sup> mice distinctly enriched for pathways associated with neuropsychiatric disorders. In the male Fgf14<sup>−/−</sup> mouse, we found molecular characteristics that, in part, may explain a previously described neurotransmission and behavioral phenotype. This includes decreased levels of ALDH1A1 and protein kinase A (PRKAR2B). ALDH1A1 has been shown to mediate an alternative pathway for gamma-aminobutyric acid (GABA) synthesis, while PRKAR2B is essential for dopamine 2 receptor signaling, which is the basis of current antipsychotics. Collectively, our results provide new insights in the role of FGF14 and support the use of the <i>Fgf14</i><sup>−/−</sup> mouse as a useful preclinical model of SZ for generating hypotheses on disease mechanisms, sex-specific manifestation, and therapy.
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