An intrastriatal brain-derived neurotrophic factor infusion restores striatal gene expression in Bdnf heterozygous mice

Abstract

Reduction in the amount of brain-derived neurotrophic factor (BDNF) in corticostriatal afferents is thought to contribute to the vulnerability of medium spiny striatal neurons in Huntington's disease. In young Bdnf heterozygous ((+/-)) mice, striatal medium spiny neurons (MSNs) express less preprodynorphin (PPD), preproenkephalin (PPE), and D(3) receptor mRNA than wildtype mice. Further, in aged Bdnf (+/-) mice, opioid, trkB receptor, and glutamic acid decarboxylase gene expression, and the number of dendritic spines on MSNs are more affected than in wildtype or younger Bdnf (+/-) mice. In this study, the possibility that intrastriatal infusions of BDNF would elevate gene expression in the striatum of Bdnf (+/-) mice was investigated. Wildtype and Bdnf (+/-) mice received a single, bilateral microinjection of BDNF or PBS into the dorsal striatum. Mice were killed 24h later and semi-quantitative in situ hybridization histochemical analysis confirmed that PPD, PPE, and D(3) receptor mRNA was less in the caudate-putamen (CPu) and nucleus accumbens (NAc) core of Bdnf (+/-) mice than in wildtype mice. A BDNF infusion increased PPD mRNA in the CPu and NAc core of wildtype mice and restored PPD mRNA levels in the NAc core of Bdnf (+/-) mice. BDNF also restored the gene expression of PPE in the CPu of Bdnf (+/-) mice to wildtype levels; however, PPE mRNA in the NAc did not differ among groups. Furthermore, BDNF increased D(3) receptor mRNA in the NAc core of wildtype and Bdnf (+/-) mice. These results demonstrate that exogenous BDNF restores striatal opioid and D(3)R gene expression in mice with genetically reduced levels of endogenous BDNF.