CELLULAR ALTERATIONS OF ADULT HIPPOCAMPAL NEUROGENESIS IN THE FGF14−/− MOUSE MODEL
Over the past decade, growing evidence indicates that adult neurogenesis (the production of functionally mature neurons from progenitor cells in the adult mammalian brain) is linked to the etiology of many neurodegenerative and psychiatric disorders. Studies have shown that neurogenesis is clearly a multifactorial and complex process that includes proliferation, differentiation, migration, maturation, and integration of newborn neurons in the adult brain circuit. However, a thorough understanding of the molecular and cellular elements at the base of adult neurogenesis remains elusive. Identifying factors, pathways, and molecules that affect multiple stages of adult neurogenesis not only would shed light on the pathogenesis of several brain illnesses but also may improve the treatment strategies against these diseases. Using a combination of BrdU incorporation studies, confocal imaging, and electrophysiology, I started looking at the potential role of the fibroblast growth factor 14 (FGF14), a disease-associated factor that controls neuronal excitability and synaptic plasticity in adult neurogenesis. It became clear that the genetic deletion of Fgf14 leads to previously undefined alterations in adult neurogenesis in the dentate gyrus (DG) of the hippocampal region. I show that FGF14 is dynamically expressed during adult neural stem cell development and genetic deletion of Fgf14 in Fgf14−/− mice leads to a significant change in the proportion of proliferating and immature and mature newly born adult granule cells. This results in an increase in the immature neuronal population and a reduction in mature neurons expressing calbindin, while early progenitor stem cells in the DG remained intact. Electrophysiological extracellular field recordings revealed reduced minimal-threshold responses and impaired paired-pulse facilitation at the perforant path to DG inputs in Fgf14−/− compared to Fgf14+/+ mice, supporting disrupted synaptic connectivity as a correlative read-out to impaired neurogenesis. I therefore started looking at the relevant mechanisms underlying these alterations of neurogenesis in the adult Fgf14−/− mice. I carried out protein binding and immunohistochemistry studies of critical molecules for neurogenesis, such as the disrupted gene in schizophrenia (DISC1). I found that FGF14 might bind DISC1 in a recombinant system and native mouse brain tissue. Disruption of this binding might be involved in the alterations of adult neurogenesis in Fgf14−/− mice. Another possible mechanism is the changes in the axon initial segment (AIS) structure; the changes themselves may result in affected circuitry that leads to impairment in adult neurogenesis. Thus, I examined a key element of the AIS, the voltage-gated sodium channel 1.6 (Nav1.6) α-subunit––an ion channel responsible for generating and propagating action potentials in mature neurons. My observations revealed a significant decrease in the Nav1.6 axonal expression level in the DG of Fgf14−/− mice. Knowing this, I gained an idea of possible molecules that play a role with FGF14 in regulating the growth of newborn neurons during adult neurogenesis. In humans, mutations of the FGF14 gene are the genetic cause of spinocerebellar ataxia 27, a complex neurodegenerative disorder associated with cognitive and motor deficits. Thus, while providing evidence for a novel regulator of adult neurogenesis, this study provides new insights into the complex pathology associated with disrupted FGF14 function, filling knowledge gaps in this emerging field of research in molecular psychiatry.