Abstract
Despite the presence of on-going neurogenesis in the adult mammalian brain, neurons are generally not replaced after injury. Using a rodent model of excitotoxic cell loss and retroviral (RV) lineage tracing, we previously demonstrated transient recruitment of precursor cells from the subventricular zone (SVZ) into the lesioned striatum. In the current study we determined that these cells included migratory neuroblasts and oligodendrocyte precursor cells (OPC), with the predominant response from glial cells. We attempted to override this glial response by ectopic expression of the pro-neurogenic genes Pax6 or Dlx2 in the adult rat SVZ following quinolinic acid lesioning. RV-Dlx2 over-expression stimulated repair at a previously non-neurogenic time point by enhancing neuroblast recruitment and the percentage of cells that retained a neuronal fate within the lesioned area, compared to RV-GFP controls. RV-Pax6 expression was unsuccessful at inhibiting glial fate and intriguingly, increased OPC cell numbers with no change in neuronal recruitment. These findings suggest that gene choice is important when attempting to augment endogenous repair as the lesioned environment can overcome pro-neurogenic gene expression. Dlx2 over-expression however was able to partially overcome an anti-neuronal environment and therefore is a promising candidate for further study of striatal regeneration.
Highlights
Compensatory adult neurogenesis has been demonstrated in many models of brain injury and neurodegeneration, including stroke, trauma, epilepsy, excitotoxic lesioning, Huntington’s and Parkinson’s disease[1,2,3,4,5,6,7,8,9]
Of oligodendrocyte precursor cells (OPCs) in response to QA-induced striatal cell loss, we investigated the effect of over-expressing the proneurogenic factors Pax6 and Dlx2
More GFP-labelled cells were recruited into the QA lesioned striatum from subventricular zone (SVZ) progenitors that were born on the day of QA lesioning or two days post QA lesion when compared to controls (Figure 1j; one way ANOVA=0.0032; Dunnett’s post hoc test between time points and control p
Summary
Compensatory adult neurogenesis has been demonstrated in many models of brain injury and neurodegeneration, including stroke, trauma, epilepsy, excitotoxic lesioning, Huntington’s and Parkinson’s disease[1,2,3,4,5,6,7,8,9]. TAPs have been found to be heterogeneous and express combinations of the pro-neurogenic genes Mash, Pax, Ngn, Dlx and the oligodendrocyte lineage gene Olig2[2, 11,12,13,14,15,16]. Neural cell loss or injury in the adult brain can alter endogenous neurogenesis and elicit a compensatory repair process. Alterations in the expression of Mash, Pax, Ngn, Dlx and/or Olig have been observed in the adult SVZ and parenchyma in various models of neural cell loss, consistent with their potential roles in the endogenous repair process[2, 8, 9, 16,17,18,19]
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