Fibroblast Growth Factor 14 is an Essential Element of the Inhibitory Circuit that Controls Cognitive Function Associated with Schizophrenia
Conference Paper
Publication Work Type:
CONFERENCE PROCEEDINGS
Publication Online URL:
Conference Name:
American College of Neuropsychopharmacology (ACNP) 54th Annual Meeting
Conference Location:
American College of Neuropsychopharmacology (ACNP) 54th Annual Meeting
Conference Date:
Wednesday, December 9, 2015
Sponsoring Organization:
American College of Neuropsychopharmacology
Publication Abstract:
Cognitive processes require gamma-amino-butyric acid (GABA) interneurons. Via complex synaptic connections, these cells regulate cellular excitability and synaptic plasticity of principal neurons, balancing the excitatory/inhibitory (E/I) tone in cortical networks. Loss of and impairment in function of parvalbumin (PV) interneurons and GABAergic synapses is associated with cognitive impairment in schizophrenia and other psychiatric disorders. Despite efforts to identify the molecular factors leading to E/I imbalance and impaired PV interneuron functioning, much remains to be learned. Additional knowledge of key regulatory nodes that control PV neuronal integrity and function, and GABAergic synapses is essential, especially to develop effective treatments for cognitive impairment. With a combination of animal model studies and post-mortem transcriptomics analysis, we provide what we believe are breakthrough results demonstrating a novel potential link between cognitive decline in schizophrenia and expression of fibroblast growth factor 14 (FGF14), a regulator of intrinsic excitability, synaptic transmission and plasticity. We show that Fgf14-/- mice have significantly reduced number of PV interneurons, decreased expression of the presynaptic GABAergic markers, GAD67 and VGAT, reduced inhibitory connections, decreased gamma frequency oscillations in cortical areas, and impaired working memory. Bioinformatics analysis of schizophrenia transcriptomics from human post-mortem tissue revealed functional co-clustering and correlative decreased expression of FGF14, PVALB, GAD67 and VGAT. Together these results provide evidence that FGF14 is a new risk-factor associated with schizophrenia and perhaps related disorders.