Age-dependent alterations of corticostriatal activity in the YAC128 mouse model of Huntington disease.
Huntington disease is a genetic neurodegenerative disorder that produces motor, neuropsychiatric, and cognitive deficits and is caused by an abnormal expansion of the CAG tract in the huntingtin (htt) gene. In humans, mutated htt induces a preferential loss of medium spiny neurons in the striatum and, to a lesser extent, a loss of cortical neurons as the disease progresses. The mechanisms causing these degenerative changes remain unclear, but they may involve synaptic dysregulation. We examined the activity of the corticostriatal pathway using a combination of electrophysiological and optical imaging approaches in brain slices and acutely dissociated neurons from the YAC128 mouse model of Huntington disease. The results demonstrated biphasic age-dependent changes in corticostriatal function. At 1 month, before the behavioral phenotype develops, synaptic currents and glutamate release were increased. At 7 and 12 months, after the development of the behavioral phenotype, evoked synaptic currents were reduced. Glutamate release was decreased by 7 months and was markedly reduced by 12 months. These age-dependent alterations in corticostriatal activity were paralleled by a decrease in dopamine D(2) receptor modulation of the presynaptic terminal. Together, these findings point to dynamic alterations at the corticostriatal pathway and emphasize that therapies directed toward preventing or alleviating symptoms need to be specifically designed depending on the stage of disease progression.
Joshi
Prasad R
PR
Mental Retardation Research Center, The David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Wu
Nan-Ping
NP
André
Véronique M
VM
Cummings
Damian M
DM
Cepeda
Carlos
C
Joyce
John A
JA
Carroll
Jeffrey B
JB
Leavitt
Blair R
BR
Hayden
Michael R
MR
Levine
Michael S
MS
Bamford
Nigel S
NS
D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D002104:Cadmium / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000503:physiopathology*; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D009434:Neural Pathways / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D015259:Dopamine Agents; D018683:Excitatory Amino Acid Agents; C073804:FM1 43; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D002104:Cadmium