Impaired TrkB Receptor Signaling Underlies Corticostriatal Dysfunction in Huntington’s Disease

Abstract

Summary Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The debilitating choreic movements that plague HD patients have been attributed to striatal degeneration induced by the loss of cortically supplied brain-derived neurotrophic factor (BDNF). Here we show that in mouse models of early symptomatic HD, BDNF delivery to the striatum and its activation of tyrosine-related kinase B (TrkB) receptors were normal. However, in striatal neurons responsible for movement suppression, TrkB receptors failed to properly engage postsynaptic signaling mechanisms controlling the induction of potentiation at corticostriatal synapses. Plasticity was rescued by inhibiting p75 neurotrophin receptor (p75NTR) signaling or its downstream target phosphatase-and-tensin-homolog-deleted-on-chromosome-10 (PTEN). Thus, corticostriatal synaptic dysfunction early in HD is attributable to a correctable defect in the response to BDNF, not its delivery.

SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease

“…For example, disruption of the CaM-KII complex with NMDAR leads to persistent reduction of the synaptic strength and weakening of hippocampal synapses (52). In this regard, our finding of impaired surface presentation of synaptic NR2A in HD MSNs is in line with reduced excitatory postsynaptic currents (EPSCs) (31), deficient striatal long-term synaptic plasticity (33), and reduced spine density of MSNs (55) observed in the zQ175 mouse model at the symptomatic stage. In addition, since NR2A-containing NMDARs have been found to have protective effects on neuronal survival (56)(57)(58), insufficient synaptic NR2A signaling could increase the vulnerability of MSNs in HD and account for the direct correlation between clinical motor impairment and striatal atrophy observed in human HD patients (59,60).…”

“…To assess whether trafficking and surface presentation of NR2A subunits is perturbed in HD MSNs, we utilized the zQ175 mouse model of HD, which includes ~188 CAG repeats contained within a chimeric human/mouse exon 1 of murine HTT gene (30) and has been well established as a robust mouse model to study molecular mechanisms and therapeutic interventions of HD (30)(31)(32)(33)(34). Here, using quantitative analysis of immuno-electron microscopy (EM), we demonstrate that in symptomatic zQ175 mice, NR2A labeling is significantly reduced on the dendritic plasma membrane and at the synapses of MSNs and it becomes more restricted to the cytoplasm of MSNs.…”

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

“…The BDNF pathway is altered in HD because of decreased transcription and release of BDNF at the corticostriatal synapses (4,38) as well as impaired TrkB receptor signaling (39). Similarly, synaptic (but not extrasynaptic) NMDARs enhance Akt phosphorylation and neuroprotection (40).…”

Primary cilia and autophagic dysfunction in Huntington’s disease

“…Deficits in BDNF-mediated downstream tyrosine-related kinase B (TrkB) signaling have also been reported. [106][107][108][109] TrkB receptor localization and activation are primary cilia-dependent processes and primary cilia loss impedes activation of TrkB. 110 Conversely, upregulation of p75 NTR signaling has been shown to disrupt TrkB signaling.…”

“…110 Conversely, upregulation of p75 NTR signaling has been shown to disrupt TrkB signaling. 106 Because p75 NTR also localizes to primary cilia 111 and is the only other known receptor for BDNF, the effect of changes in ciliary-mediated signal transduction in HD merits further examination.…”