BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington's disease mice

Anton Reiner, H. B. Wang, N. Del Mar, Kazuko Sakata, W. Yoo, Yunping Deng

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

We have found that daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGluR2/3 agonist LY379268 (20 mg/kg) beginning at 4 weeks dramatically improves the phenotype in R6/2 mice. For example, we observed normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 1520% striatal neuron loss at 10 weeks. As acute LY379268 treatment is known to increase cortical BDNF production, and BDNF is known to be beneficial for striatal neurons, we investigated if the benefit of daily LY379268 in R6/2 mice for striatal projection neurons was associated with increases in corticostriatal BDNF, with assessments done at 10 weeks of age after daily MTD treatment since the fourth week of life. We found that LY379268 increased BDNF expression in layer 5 neurons in motor cortex, which project to striatum, partly rescued a preferential loss of enkephalinergic striatal neurons, and enhanced substance P (SP) expression by SP striatal projection neurons. The enhanced survival of enkephalinergic striatal neurons was correlated with the cortical BDNF increase, but the enhanced SP expression by SP striatal neurons was not. Thus, LY379268 may protect the two main striatal projection neuron types by different mechanisms, enkephalinergic neurons by the trophic benefit of BDNF, and SP neurons by a mechanism not involving BDNF. The SP neuron benefit may perhaps instead involve the anti-excitotoxic action of mGluR2/3 receptor agonists.

Original languageEnglish (US)
Pages (from-to)161-172
Number of pages12
JournalBrain Research
Volume1473
DOIs
StatePublished - Sep 14 2012

Fingerprint

LY 379268
Corpus Striatum
Huntington Disease
Brain-Derived Neurotrophic Factor
Neurons
Substance P
Maximum Tolerated Dose
metabotropic glutamate receptor 2
Aptitude
Motor Cortex
Subcutaneous Injections

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

@article{71bbed22f6f944ae9f6939e79319222f,
title = "BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington's disease mice",
abstract = "We have found that daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGluR2/3 agonist LY379268 (20 mg/kg) beginning at 4 weeks dramatically improves the phenotype in R6/2 mice. For example, we observed normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 1520{\%} striatal neuron loss at 10 weeks. As acute LY379268 treatment is known to increase cortical BDNF production, and BDNF is known to be beneficial for striatal neurons, we investigated if the benefit of daily LY379268 in R6/2 mice for striatal projection neurons was associated with increases in corticostriatal BDNF, with assessments done at 10 weeks of age after daily MTD treatment since the fourth week of life. We found that LY379268 increased BDNF expression in layer 5 neurons in motor cortex, which project to striatum, partly rescued a preferential loss of enkephalinergic striatal neurons, and enhanced substance P (SP) expression by SP striatal projection neurons. The enhanced survival of enkephalinergic striatal neurons was correlated with the cortical BDNF increase, but the enhanced SP expression by SP striatal neurons was not. Thus, LY379268 may protect the two main striatal projection neuron types by different mechanisms, enkephalinergic neurons by the trophic benefit of BDNF, and SP neurons by a mechanism not involving BDNF. The SP neuron benefit may perhaps instead involve the anti-excitotoxic action of mGluR2/3 receptor agonists.",
author = "Anton Reiner and Wang, {H. B.} and {Del Mar}, N. and Kazuko Sakata and W. Yoo and Yunping Deng",
year = "2012",
month = "9",
day = "14",
doi = "10.1016/j.brainres.2012.07.026",
language = "English (US)",
volume = "1473",
pages = "161--172",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",

}

TY - JOUR

T1 - BDNF may play a differential role in the protective effect of the mGluR2/3 agonist LY379268 on striatal projection neurons in R6/2 Huntington's disease mice

AU - Reiner, Anton

AU - Wang, H. B.

AU - Del Mar, N.

AU - Sakata, Kazuko

AU - Yoo, W.

AU - Deng, Yunping

PY - 2012/9/14

Y1 - 2012/9/14

N2 - We have found that daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGluR2/3 agonist LY379268 (20 mg/kg) beginning at 4 weeks dramatically improves the phenotype in R6/2 mice. For example, we observed normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 1520% striatal neuron loss at 10 weeks. As acute LY379268 treatment is known to increase cortical BDNF production, and BDNF is known to be beneficial for striatal neurons, we investigated if the benefit of daily LY379268 in R6/2 mice for striatal projection neurons was associated with increases in corticostriatal BDNF, with assessments done at 10 weeks of age after daily MTD treatment since the fourth week of life. We found that LY379268 increased BDNF expression in layer 5 neurons in motor cortex, which project to striatum, partly rescued a preferential loss of enkephalinergic striatal neurons, and enhanced substance P (SP) expression by SP striatal projection neurons. The enhanced survival of enkephalinergic striatal neurons was correlated with the cortical BDNF increase, but the enhanced SP expression by SP striatal neurons was not. Thus, LY379268 may protect the two main striatal projection neuron types by different mechanisms, enkephalinergic neurons by the trophic benefit of BDNF, and SP neurons by a mechanism not involving BDNF. The SP neuron benefit may perhaps instead involve the anti-excitotoxic action of mGluR2/3 receptor agonists.

AB - We have found that daily subcutaneous injection with a maximum tolerated dose (MTD) of the mGluR2/3 agonist LY379268 (20 mg/kg) beginning at 4 weeks dramatically improves the phenotype in R6/2 mice. For example, we observed normalization of motor function in distance traveled, speed, the infrequency of pauses, and the ability to locomote in a straight line, and a rescue of a 1520% striatal neuron loss at 10 weeks. As acute LY379268 treatment is known to increase cortical BDNF production, and BDNF is known to be beneficial for striatal neurons, we investigated if the benefit of daily LY379268 in R6/2 mice for striatal projection neurons was associated with increases in corticostriatal BDNF, with assessments done at 10 weeks of age after daily MTD treatment since the fourth week of life. We found that LY379268 increased BDNF expression in layer 5 neurons in motor cortex, which project to striatum, partly rescued a preferential loss of enkephalinergic striatal neurons, and enhanced substance P (SP) expression by SP striatal projection neurons. The enhanced survival of enkephalinergic striatal neurons was correlated with the cortical BDNF increase, but the enhanced SP expression by SP striatal neurons was not. Thus, LY379268 may protect the two main striatal projection neuron types by different mechanisms, enkephalinergic neurons by the trophic benefit of BDNF, and SP neurons by a mechanism not involving BDNF. The SP neuron benefit may perhaps instead involve the anti-excitotoxic action of mGluR2/3 receptor agonists.

UR - http://www.scopus.com/inward/record.url?scp=84865496594&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865496594&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2012.07.026

DO - 10.1016/j.brainres.2012.07.026

M3 - Article

VL - 1473

SP - 161

EP - 172

JO - Brain Research

JF - Brain Research

SN - 0006-8993

ER -