p75NTR in Huntington's disease: beyond the basal ganglia

Huntington's disease (HD) is a fatal neurodegenerative disorder with a characteristic phenotype including chorea and dystonia, uncoordinated fine movements, cognitive decline and psychiatric disturbances. Even though the clinical diagnosis of HD relies on the manifestation of motor abnormalities, the associated memory impairments have been growing in prominence. Indeed, cognitive deficits are evident along all the disease process even in the prodrome before any motor diagnosis is given. These clinical signs have been mainly attributed to corticostriatal dysfunction being deficits of neurotrophic support, caused by either reduced levels of brain-derived neurotrophic factor (BDNF) [1] or decreased TrkB and aberrant p75 NTR signalling [2, 3], one of the major pathogenic mechanism involved. However, in recent years has emerged the idea that cognitive decline in HD is likely a reflection of a widespread brain circuitry defect rather than a basal ganglia dysfunction per se. In this regard, in our recent studies we shed new light on the contribution of the hippocampal circuitry to synaptic and memory decline in HD. We demonstrated hippocampal dysfunction in a precise genetic HD mouse model that expresses endogenous levels of mutant huntingtin, Hdh Q7/ Q111 mice, manifested as alterations in spatial, recognition and associative memories. To get insight into the molecular mechanisms underlying such defects, we focused on p75 NTR since growing evidence indicate that p75 NTR plays an antagonistic role in synaptic plasticity. We demonstrated up-regulation of p75 NTR in the hippocampus of distinct HD mouse models and in human brain without evident changes in the cortex, which extends our previous data showing increased p75 NTR expression in the HD striatum [4]. In agreement with a critical role of aberrant p75 NTR expression in hippocampal dysfunction we found preserved spatial, recognition and associative memories in new double-mutant mice expressing mutant huntingtin but " physiological " levels of p75 NTR levels (Hdh Q7/Q111 :p75+/-mice). How aberrant p75 NTR levels may mediate synaptic and memory deficits in HD is an intriguing question. On one hand, our results indicated that p75 NTR directly or indirectly regulate the expression of different synaptic-related proteins previously implicated in HD synaptic and/or cognitive deficits, such as CBP, CamKII, GluA1 or BDNF since memory improvements in double mutant Hdh Q7/Q111 :p75 +/-mice correlated with a recovery of the expression and/or phosphorylation of these molecules. On the other, the loss of dendritic spines in CA1 pyramidal neurons exhibited by Hdh Q7/Q111 mutant mice was also prevented …