Neurotrophin receptor p75^NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

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Abstract

Learning and memory deficits are early clinical manifestations of Huntington’s disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75^NTR negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75^NTR function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75^NTR are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75^NTR levels in HD mutant mice heterozygous for p75^NTR prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75^NTR in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75^NTR in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75^NTR mediates synaptic, learning, and memory dysfunction in HD.

Authors

Verónica Brito, Albert Giralt, Lilian Enriquez-Barreto, Mar Puigdellívol, Nuria Suelves, Alfonsa Zamora-Moratalla, Jesús J. Ballesteros, Eduardo D. Martín, Nuria Dominguez-Iturza, Miguel Morales, Jordi Alberch, Sílvia Ginés