Brain-derived neurotrophic factor (
BDNF) mediates neuron growth and is regulated by
adenylyl cyclases (ACs). Mice lacking AC1/8 (DKO) have a basal reduction in the dendritic complexity of medium spiny neurons in the caudate putamen and demonstrate increased neurotoxicity in the striatum following acute neonatal
ethanol exposure compared to wild type (WT) controls, suggesting a compromise in
BDNF regulation under varying conditions. Although neonatal
ethanol exposure can negatively impact
BDNF expression, little is known about the effect on
BDNF receptor activation and its downstream signaling, including Akt activation, an established neuroprotective pathway. Therefore, here we determined the effects of AC1/8 deletion and neonatal
ethanol administration on
BDNF and proBDNF
protein expression, and activation of
tropomyosin-related
kinase B (TrkB), Akt, ERK1/2, and PLCγ. WT and DKO mice were treated with a single dose of 2.5 g/kg
ethanol or saline at postnatal days 5-7 to model late-gestational alcohol exposure. Striatal and cortical tissues were analyzed using a
BDNF enzyme-linked
immunosorbent assay or immunoblotting for proBDNF, phosphorylated and total TrkB, Akt, ERK1/2, and PLCɣ1. Neither postnatal
ethanol exposure nor AC1/8 deletion affected total
BDNF protein expression at any time point in either region examined. Neonatal
ethanol increased the expression of proBDNF
protein in the striatum of WT mice 6, 24, and 48 h after exposure, with DKO mice demonstrating a reduction in proBDNF expression 6 h after exposure. Six and 24 h after
ethanol administration, phosphorylation of full-length TrkB in the striatum was significantly reduced in WT mice, but was significantly increased in DKO mice only at 24 h. Interestingly, 48 h after
ethanol, both WT and DKO mice demonstrated a reduction in phosphorylated full-length TrkB. In addition, Akt and PLCɣ1 phosphorylation was also decreased in
ethanol-treated DKO mice 48 h after injection. These data demonstrate dysregulation of a potential survival pathway in the AC1/8 knockout mice following early-life
ethanol exposure.