Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: involvement of phospholipaseCgamma activity and glutamate receptor expression.
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.
Giralt
A
A
Departament de Biologia Cellular i Anatomia Patològica, Universitat de Barcelona, Casanova 143, E-08036 Barcelona, Spain.
Rodrigo
T
T
Martín
E D
ED
Gonzalez
J R
JR
Milà
M
M
Ceña
V
V
Dierssen
M
M
Canals
J M
JM
Alberch
J
J
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003072:Cognition Disorders / Q000235:genetics / Q000503:physiopathology*; D004193:Discrimination Learning / Q000502:physiology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D000071058:Huntingtin Protein; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D018408:Patch-Clamp Techniques / Q000379:methods; D051966:Phospholipase C gamma / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013550:Swimming
D019208:Brain-Derived Neurotrophic Factor; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051966:Phospholipase C gamma; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C506812:Htt protein, mouse; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor