Impaired basal and running-induced hippocampal neurogenesis coincides with reduced Akt signaling in adult R6/1 HD mice
Introduction
Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder. The pathophysiology of HD manifests primarily in the brain with progressive symptomology that includes cognitive, psychiatric and motor dysfunction (Borrell-Pages et al., 2006, Cattaneo et al., 2005, HDCRG, 1993, Reiner et al., 1988). The onset of HD typically occurs in the adult with a disease outcome that is invariably fatal. At the genetic level HD results from an expanded cytosine–adenine–guanine (CAG) trinucleotide repeat that encodes a poly-glutamine (polyQ) tract in the N-terminus of the huntingtin protein (Hatters, 2008, HDCRG, 1993). The expanded polyQ stretch imparts a propensity for the mutant huntingtin protein (mHtt) to form intracellular aggregates and proteolytic cleavage allows mutant fragments to enter the nucleus and form protein aggregates (Wellington et al., 1998). The presence of polyQ-containing aggregates in the brain is a pathological hallmark of HD and is postulated to contribute to neuronal dysfunction and death (Davies et al., 1997). The R6/1 transgenic mouse line closely models human HD, including the development of aggregates, and provides an important platform to study underlying disease mechanisms and therapeutic strategies (Gil and Rego, 2009).
Cell-based approaches remain a focus of therapeutic intervention for HD, which hitherto remains without effective therapeutic intervention (Clelland et al., 2008). However, cell-based therapy for HD has had equivocal outcomes and preclinical studies are paramount in developing effective neural regeneration approaches. The emergence of adult neurogenesis as an endogenous neuronal repair mechanism has provided therapeutic appeal to a variety of neurodegenerative disorders including HD (Vandenbosch et al., 2009). Adult neurogenesis ensues throughout the life of mammals in discreet niches, including the sub-granular zone (SGZ) of the hippocampus. Adult hippocampal neurogenesis (AHN) is postulated to be an important neuronal substrate mediating the positive effects of running and enrichment on learning and memory (Lafenetre et al., 2011). Deficits in AHN have been demonstrated in several rodent models of HD (Gil et al., 2004, Gil et al., 2005, Lazic et al., 2004, Simpson et al., 2011) and reviewed in Gil-Mohapel et al. (2011). AHN deficits in the R6/1 HD transgenic mouse model manifest progressively and could underlie the impaired cognitive and depressive-like behaviors that develop in this mouse model (Grote et al., 2005, Lazic et al., 2004, Lazic et al., 2006, Ransome et al., 2012).
A diversity of environmental, physiological and genetic factors contributes to the regulation of AHN levels. Exercise in the form of voluntary running stimulates neuronal precursor proliferation to increase AHN levels and improve cognition (Ransome and Turnley, 2008, van Praag et al., 1999a, van Praag et al., 1999b). R6/1 HD mice given access to voluntary running have sex-dependent responses to exercise-induce neurotrophin expression (Zajac et al., 2010). However, whether sex is a determinant of exercise-induced AHN in R6/1 HD mice remains unknown. Cognitive stimulation through environmental enrichment also increases AHN levels but does so by promoting neuronal survival (Kempermann et al., 1997). Although R6/1 HD mice remain responsive to environmental enrichment strategies aimed at improving AHN and cognition (Lazic et al., 2004, Lazic et al., 2006, Nithianantharajah et al., 2008, Pang et al., 2006), there remains a paucity of evidence demonstrating functional AHN. Our current study was performed to examine whether sex affects basal or running-induced AHN in R6/1 HD and wildtype mice and determine whether adult-generated hippocampal neurons express c-Fos in R6/1 HD mice.
Section snippets
Voluntary running levels are reduced in R6/1 HD mice
Female and male mice from each genotype placed into voluntary running groups had their wheel activity digitally monitored and recorded daily in the form of distance run/24-h over 8 consecutive days (Fig. 2). Daily tracking of running distances showed that female R6/1 HD mice ran consistently less than female wildtype mice, with days 1, 2, 4, 5 and 6 showing significant decreases (Fig. 2A). A similar comparison showed a more severe deficit in voluntary running activity in male R6/1 HD animals
Discussion
The cellular and molecular mechanisms that underlie HD pathophysiology are not fully understood. Several HD mouse models exhibit AHN deficits, which if restored, could provide therapeutic efficacy dependent on the ability of these adult-generated neurons to functionally integrate (Ransome et al., 2012). Furthermore, accumulating evidence points toward sexual dimorphism in HD behavioral deficits in which AHN may play a role (Ransome et al., 2012). Hence, our current study examined the response
Conclusion
Our current data extends previous studies examining AHN deficits in R6/1 HD mice. We showed that proliferation of hippocampal neural precursors is impaired equally in female and male R6/1 HD mice. While both sexes of R6/1 HD mice have reduced voluntary running activity, the deficits were more severe in males. Reduced running distances could partly explain the attenuated and non-significant running-induced AHN in female R6/1 HD mice, with reduced hippocampal Akt activity being a potential
Animals
Female and male R6/1 HD transgenic mice on the CBA/BL6 genetic background and CBA/BL6 wildtype littermates were obtained from stocks maintained at the Howard Florey Institute. Over-expression of exon 1 of the human huntingtin gene with approximately 125 CAG repeats driven by the human huntingtin promoter in R6/1 HD mice provides an accurate model of human adult-onset HD (Gil and Rego, 2009, Mangiarini et al., 1996). Rear-paw clasping is a behavioral trait indicative of motor dysfunction in R6/1
Conflict of interest
There are no conflicts of interest.
Acknowledgments & funding source
National Health and Medical Research Council project grant number: 509031 (AJH).
MIR is supported by a National Health and Medical Research Council Australian Biomedical Fellowship (ID: 628868) and AJH is supported by an Australian Research Council Future Fellowship and is an Honorary National Health and Medical Research Council Senior Research Fellow. The funders had no role in study design, data collection and analysis, decision to publish or manuscript preparation.
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