• The role of HGF/SF-Met on forebrain GABAergic interneuron development

      Martins, Gabriela J.; Powell, Elizabeth M. (Elizabeth Mary) (2009)
      Integrating activity across various brain regions is critical for supporting adaptive behavior. GABAergic interneurons are critical for modulating information processing in each brain region. Recent research suggests that GABAergic interneuron development and the subsequent organization of neural circuitry may be altered in neuropsychiatric disorders such as autism. The hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, Met, have been genetically linked to an autism susceptibility loci and further implicated in the development of the mouse forebrain. In this study, I define the role of HGF/SF in the development of GABAergic interneurons and the subsequent behavioral consequences. HGF/SF, when bound to Met, induces a signaling cascade that can act as a chemoattractant, or a general promoter of cell movement or proliferation in neural tissues. HGF/SF and Met are expressed in the developing telencephalon and alterations in HGF/SF or Met expression appear to modulate proliferation and migration patterns of interneurons. Changes to these mechanisms via HGF/SF-Met signaling lead to alterations in GABAergic interneuron numbers in the adult forebrain, specifically due to altered interneuron migration embryonically. Furthermore, the loss of Met signaling results in aberrantly splayed thalamocortical axon tracts possibly leading to mistargeting of signals in the cortex. Our data suggest that Hgf and Met are required in the embryonic mouse forebrain for the proper development of various systems that are integral to proper neural circuitry formation. Early perturbations to the HGF/SF-Met signaling system in the embryo alter the development of GABAergic interneurons leading to long-term cognitive impairments.