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

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 15–20% 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.

► The striatal neurons lost in R6/2 mice represent ENK neurons but not SP neurons.
► Daily LY379268 treatment boosts BDNF in cortical layer 5 neurons in R6/2 mice.
► LY379268 may protect striatal ENK neurons by enhancing BDNF delivery to striatum.
► LY379268 may protect striatal SP neurons by a presynaptic anti-excitotoxic action.
► Daily LY379268 protects striatum and delays the R6/2 behavioral phenotype.