Trimethyltin-induced neurogenesis in the murine hippocampus

Abstract

Neurogenesis continues to occur in the mature rodent brain with one of the most prominent sources for new neurons being the subgranular layer (SGL) of the dentate gyrus (DG) in the hippocampus. A number of factors can stimulate this process including synaptic activity and injury. To determine if this process would occur upon a direct injury to the dentate region, we exposed young, 21 day old male CD-1 mice to the hippocampal toxicant, trimethyltin (TMT). An acute i.p. injection of TMT (2 mg/kg) produced extensive damage and loss of dentate granule neurons within 72 h. This active period of degeneration was accompanied by an increase in the generation of progenitor cells within the SGL as identified by BrdU uptake and Ki-67 immunostaining. As additional markers for neurogenesis, both nestin and doublecortin showed increased staining patterns within the blades of the dentate. In these young weanling mice, the level of proliferation was sufficient to significantly repopulate the dentate region by 4 weeks post-TMT, suggesting a high level of regenerative potential. Our data indicate a significant level of neurogenesis occurring during the active process of degeneration and in an environment of microglia activation. The TMT-induced injury offers a model system for further examination of the process of neurogenesis, neural adaptation, and the influence of inflammatory factors and glia interactions.

Temporally specific proliferation events are induced in the hippocampus following acute focal injury

“…In virtually all models of brain trauma, with the exception of focal injury (Gould and Tanapat, 1997), increases in neurogenesis in the DG are observed only following a latent period greater than 24 hr (Parent et al, 1997;Ferland et al, 2002;Parent, 2003;Harry et al, 2004). This suggests that focal injury to the DG initiates a rapid increase in neurogenesis, whereas more global (and diffuse) injuries do not.…”

“…An increase in the rate of neurogenesis has been shown in the DG with a number of models of brain injury, including following global ischemia (Jin et al, 2001;Kee et al, 2001), seizures (Bengzon et al, 1997;Parent et al, 1997;Scott et al, 2000;Ferland et al, 2002), kainic and ibotenic acid injections (Gould and Tanapat, 1997;Gray and Sundstrom, 1998), trimethyltin injections (Harry et al, 2004), and blunt trauma (Dash et al, 2001;Rice et al, 2003). With global models of brain damage, an increase in the rate of neurogenesis in the DG is seen only after a latent period that lasts for more than 24 hr (for review see Parent, 2003).…”

The Yin and Yang of Microglia

“…In parallel with their negative or neurotoxic effects, microglia also play an important role in the maintenance of neuronal wellbeing [52,152]. Based on their phagocytic function as the ‘professional’ phagocytes of the CNS, microglia can enter damaged brain regions and remove toxic byproducts, invading pathogens and cell debris.…”

Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin

“…Nilsberth et al 2002). A substantial body of research also suggests that TMT lesions share molecular hallmarks and pathophysiological mechanisms of Alzheimer's disease (AD), including the altered expression of the amyloid precursor protein, presenilin-1 and c-fos observed in the rat limbic system after TMT treatment (Woodruff and Baisden 1994;Fiedorowicz et al 2001;Nilsberth et al 2002;Harry et al 2004;Ogita et al 2005;Liu et al 2006). More recently Liu et al (2006) showed that in both AD patients and TMT-treated rats, the expression of microsomal epoxide hydrolase, a xenobiotic metabolizing enzyme, significantly increased in the brain areas characterized by major damage, i.e.…”