Analysis of learning memory mechanism in phenylketonuria with the CAMP/PKA/CREB/BDNF pathway in female and male rats

Phenylketonuria is a rare hereditary metabolic disease characterized by deficiency of phenylalanine hydroxylase. The absence of enzyme causes blood phenylalanine levels to rise. If patients are not treated, irreversible neurological damage can occur due to the accumulation of phenylalanine in the brain and, learning memory may be adversely affected. The hippocampus plays important roles in brain functions, including learning and memory. The cAMP/PKA/ CREB/BDNF pathway is associated with long-term learning and memory. In this thesis, the learning memory mechanism in phenylketonuria was examined through the cAMP/PKA/CREB/BDNF pathway in female and male rats. Phenylalanine hydroxylase enzyme inhibitor 4-Cl-phenylalanine and phenylalanine were applied to 6 day old rats by subcutaneous injection to establish rat phenylketonuria model. Locomotor activity, new object recognition and passive avoidance tests were performed to measure learning memory functions. Hippocampal metabolite concentrations, protein expressions of cAMP/PKA/CREB/pCREB/BDNF and mRNA expressions of PKA, CREB, BNDF, AChE and BChE were analyzed. Male rats displayed reduced locomotor activity compared to females. RT-qPCR results exhibited decreased AChE, BChE, CREB and BNDF mRNA levels in males along with CREB and BNDF levels in females. In protein analysis PKA activity was decreased in male rats whereas it increased in female rats. While the pCREB/CREB ratio was statistically increased in female PKU rats in male rats an increase trend was found. Our results display that in PKU model BNDF pathway and the levels of cholinergic system elements may differ by gender.