DISRUPTION OF THE HIPPOCAMPAL GABAERGIC SYSTEM IN THE Fgf14 ̶ / ̶ MOUSE MODEL
Alshammari, Tahani K
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In CNS, cognitive function is greatly dependent on the functional integrity of gamma-amino-butyric acid (GABA) interneurons. These inhibitory interneurons modulate synaptic plasticity and intrinsic excitability of principal neurons balancing the excitatory/inhibitory ratio in the brain. Reduction in parvalbumin interneurons (PVIs) and GABAergic synapses function lead to desynchronized neuronal circuits associated with cognitive deficit across many neuropsychiatric diseases, such as schizophrenia. Yet, the mechanisms underlying the loss in PVIs and E/I imbalance are not completely understood. Here, I demonstrate that the genetic ablation of the intracellular fibroblast growth factor 14 (FGF14), a molecule required for proper neuronal development, excitability, synaptic plasticity and cognitive function, leads to a reduction in PVIs in the hippocampal CA1 area, accompanied by declined expression of GABAergic presynaptic components, the glutamic acid decarboxylase 67 (GAD67) and the vesicular GABA transporter (VGAT). In addition, the CA1 GABAergic inhibitory transmission is disrupted. These cellular phenotypes coincide with reduced in vivo oscillations at gamma wave, and spatial working memory deficit. Also, the bioinformatics studies of schizophrenia transcriptomics indicated a functional co-clustering of GABAergic genes and FGF14 with correlative decreased expression of FGF14, PVALB, GAD67 and VGAT. Next, I expand these studies to examine GABAergic postsynaptic proteins that are relevant to cognitive impairment such as gephyrin, GABAA alpha-1, and alpha-2 receptor subunits. Interestingly, the results indicate genetic deletion of Fgf14 exhibit fewer effects on GABAergic postsynaptic components. Suggesting a potential role of FGF14 in regulating the GABAergic pre and postsynaptic components. Several lines of evidence support a neurodevelopmental hypothesis of schizophrenia. Although the neurodevelopmental model theory is fully appreciated, it is not well understood. So far, our studies suggest that Fgf14-/-exhibits some of the aspects of schizophrenia. Thus, to provide a better understanding of putative developmental changes in Fgf14-/-, I quantified the age-related changes in PV expression in the hippocampus. Our results indicate that genetic deletion of Fgf14 might impairs the maturation of PVIs. These findings suggest that Fgf14-/- mice exhibit molecular, cellular, functional, and developmental features associated with psychiatric disorders, and the loss of FGF14 function might be linked to the etiology of cognitive impairment and complex psychiatric disorders such as schizophrenia.