Role for RitGTPAses Signaling in Forebrain Neurogenesis Following Traumatic Brain Injury

Acquired brain injuries, such as those resulting from trauma, are among the most CQmmon causes of death and long-term disability in all age groups. Neural progenitor ceUs (NPCs) from the subventricular zone and the hippocampal dentate gyrus subgranular zone (SGZ) constantly generate new neurons throughout life, and are widely believed to contribute to endogenous repair after many types of brain injury. TBI results in a massive loss of newborn hippocampal neurons, followed by an increase in proliferation and neuronal differentiation of NPCs which has been shown to contribute to cognitive recovery. The mechanisms underlying Tal-induced immature neuron death and subsequent upregulation of neul'ogenesis are unclear. Here we provide novel data that the Rit GTPase plays a qritical role in adult neurogenesis after injury, protecting immature hippocampal neurons within the SGZ following TBI. We further demonstrate that Rit deficiency renders immature neurons vulnerable to oxidative stress in vitro. Injury-enhanced neurogenesis is associated with enhanced expression of several trophic factors following TBI. including insulin-like growth factor-l (IGF-I). Rit loss selectively impairs lGF-I, but not BDNF-dependent signaling, supporting a central role for Rit in lOP-I-mediated neufogenesis. These data motivate the hypothesis that Rit signaling plays a key role in adult neurogenesis following TBI, promoting both acute phase immature neuron survival and contributing to neurogenesis-mediated recovery. In AimJ., we use BrdU pre-labeling paradigms in Rit knockout (Rif') and active Rit expressing mice to examine the role of Rit in the acute survival of NPCs and immature neurons of the SGZ and SVZ after contusion brain injury, and use in vitro approaches to determine essential components of survival signaling dependent on Rit. In Aim..2. we evaluate the contribution of Rit signaling to posttraumatic upregulation of neurogenesis, quantifying the time course of proliferation of NPCs, their neuronal differentiation and long-term survival in Rir/-and wild-type mice. Studies will also examine the impact of Rit loss, and active Rit expression on spatialleamillglmemory. We will then evaluate the specific role(s) of Rit in directing (a) lGF-I-mediated hippocampal neurQn signaling in vitro and (b) IGF-I-stimulated neurogenesis in vivo. Significance: We propose to evaluate. for the first time, the role of Rit-mediated signaling in TBI, exploring its potential roles in protecting newborn neurons after trauma and enhancing adult neurogenesis. This work will enhance our understanding of the mechanisms of neuronal survival ill response to injury, provide novel insights into the regulation of adult neurogenesis. and identify signaling pathways that might be manipulated to improve recovery after brain injury.