Abstract
The principal projection neurons of the striatum are critically dependent on an afferent supply of brain derived neurotrophic factor (BDNF) for neurotrophic support. These neurons express TrkB, the cognate receptor for BDNF, which activates signaling pathways associated with neuronal survival and phenotypic maintenance. Impairment of the BDNF-TrkB pathway is suspected to underlie the early dysfunction and prominent degeneration of striatal neurons in Huntington disease (HD). Some studies in HD models indicate that BDNF supply is reduced, while others suggest that TrkB signaling is impaired earlier in disease progression. It remains important to determine whether a primary defect in TrkB signaling underlies reduced neurotrophic support and the early vulnerability of striatal neurons in HD. Using the transgenic R6/2 mouse model of HD we found that prior to striatal degeneration there are early deficits in striatal protein levels of activated phospho-TrkB and the downstream-regulated protein DARPP-32. In contrast, total-TrkB and BDNF protein levels remained normal. Primary neurons cultured from R6/2 striatum exhibited reduced survival in response to exogenous BDNF applications. Moreover, BDNF activation of phospho-TrkB and downstream signal transduction was attenuated in R6/2 striatal cultures. These results suggest that neurotrophic support of striatal neurons is attenuated early in disease progression due to defects in TrkB signal transduction in the R6/2 model of HD.
Highlights
Huntington’s disease (HD) is a progressive autosomal dominant disease characterized by early hyperkinetic movements and behavioral changes (Roze et al, 2011)
Since the survival and maintenance of medium spiny neurons (MSNs) are especially dependent on the brain derived neurotrophic factor (BDNF)-TrkB signaling pathway (Ivkovic and Ehrlich, 1999; Baydyuk et al, 2011), reduced neurotrophic support may underlie the early vulnerability of MSNs to degeneration in Huntington disease (HD)
We found that the normal trophic effects of BDNF on striatal neurons were attenuated in R6/2 cultures
Summary
Huntington’s disease (HD) is a progressive autosomal dominant disease characterized by early hyperkinetic movements and behavioral changes (Roze et al, 2011). In HD patients and animal models mutant huntingtin (mhtt) is expressed by a wide variety of neuronal populations with no clear preference for the vulnerable MSNs population (Trottier et al, 1995; Bhide et al, 1996). Evidence in cellular and animal models of HD and in HD (Raymond et al, 2011; Francelle et al, 2014) indicate mhtt expression is associated with forebrain abnormalities in glutamatergic and dopaminergic transmission (Bibb et al, 2000; Cepeda et al, 2014), dysregulation of gene transcription (Neueder and Bates, 2014), altered striatal enriched proteins (e.g., PDE10A, STEP, Rhes; Subramaniam et al, 2009; Saavedra et al, 2011; Leuti et al, 2013; Mealer et al, 2014; Fusco and Giampà, 2015) and impaired neurotrophic support (e.g., BDNFTrkB pathway; Zuccato et al, 2001; Wild and Tabrizi, 2014). Since the survival and maintenance of MSNs are especially dependent on the BDNF-TrkB signaling pathway (Ivkovic and Ehrlich, 1999; Baydyuk et al, 2011), reduced neurotrophic support may underlie the early vulnerability of MSNs to degeneration in HD
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