NeuroscienceJan 6, 2009

Brain-derived neurotrophic factor influences how mutant huntingtin affects thinking abilities through changes in cell signaling and glutamate receptors

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Updated Apr 4, 2026

Abstract

R6/1:BDNF+/- mice exhibited earlier and more pronounced cognitive impairment compared to R6/1 mice starting at 5 weeks of age.

BDNF may influence cognitive function even before motor symptoms appear in Huntington's disease.
Cognitive deficits were observed in discrimination and procedural learning tasks at 5 weeks of age, and in alternation learning at 9 weeks of age.
All mutant mouse genotypes displayed reduced long-term potentiation (LTP) in the hippocampus compared to wild type, with no differences among the mutant genotypes.
A decrease in phospholipaseCgamma activity was noted in R6/1, BDNF+/- and R6/1:BDNF+/- hippocampus when LTP was altered, although ERK activity remained unchanged.
Specific reductions in glutamate receptors NR1, NR2A, and GluR1 were found only in the hippocampus of R6/1:BDNF+/- mice.

Simplified

The involvement of brain-derived neurotrophic factor (BDNF) in cognitive processes and the decrease in its expression in Huntington's disease suggest that this neurotrophin may play a role in learning impairment during the disease progression. We therefore analyzed the onset and severity of cognitive deficits in two different mouse models with the same mutant huntingtin but with different levels of BDNF (R6/1 and R6/1:BDNF+/- mice). We observed that BDNF modulates cognitive function in different learning tasks, even before the onset of motor symptoms. R6/1:BDNF+/- mice showed earlier and more accentuated cognitive impairment than R6/1 mice at 5 weeks of age in discrimination learning; at 5 weeks of age in procedural learning; and at 9 weeks of age in alternation learning. At the earliest age at which cognitive impairment was detected, electrophysiological analysis was performed in the hippocampus. All mutant genotypes showed reduced hippocampal long term potentiation (LTP) with respect to wild type but did not show differences between them. Thus, we evaluated the involvement of BDNF-trkB signaling and glutamate receptor expression in the hippocampus of these mice. We observed a decrease in phospholipaseCgamma activity, but not ERK, in R61, BDNF+/- and R6/1:BDNF+/- hippocampus at the age when LTP was altered. However, a specific decrease in the expression of glutamate receptors NR1, NR2A and GluR1 was detected only in R6/1:BDNF+/- hippocampus. Therefore, these results show that BDNF modulates the learning and memory alterations induced by mutant huntingtin. This interaction leads to intracellular changes, such as specific changes in glutamate receptors and in BDNF-trkB signaling through phospholipaseCgamma.

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Brain-derived neurotrophic factor influences how mutant huntingtin affects thinking abilities through changes in cell signaling and glutamate receptors

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