The Effects of the Gsk-3 Inhıbıtor Tdzd-8 on Bıpolar-Lıke Behavıoral Phenotype Induced by Hıgh Fructose Corn Syrup Consumptıon in Adolescent Rats

Abstract

Children and adolescents are the top consumers of high fructose corn syrup (HFCS) sweetened beverages. Even though the cardiometabolic consequences of HFCS consumption in adolescents are well characterized, the neuropsychiatric consequences have yet to be determined. Adolescent rats were fed with 11% weight/volume carbohydrate containing HFCS solution, which is strikingly similar to the sugar-sweetened beverages of human consumption. HFCS-fed adolescent rats displayed bipolar-like behavioral phenotype along with hyperexcitability in hippocampal CA3-CA1 synapses. This synaptic hyperexcitability was associated with increased presynaptic release probability and increased pool of AMPA receptors to be incorporated to the postsynaptic membrane, possibly due to decreased expression of the neuron-specific α3-subunit of Na+/K+- ATPase (NKA) to 18±7% of control and an increased ser845-phosphorylation of GluR1 subunits of AMPA receptors to 4.6±1.25 times of control, respectively. TDZD-8 treatment was found to restore behavioral and electrophysiological disturbances associated with HFCS consumption by inhibition of Glycogen Synthase Kinase-3 (GSK- 3), the most probable mechanism of action of lithium for its mood-stabilizing effects. Even though hippocampal neuroinflammation and local insulin resistance were suggested as other mechanistic links tying HFCS consumption to the emergence of bipolar-like behavioral phenotype, we failed to show such a link. This dissertation showed that HFCS consumption in adolescent rats led to bipolar-like behavioral phenotype with neuronal hyperexcitability, which is known to be one of the earliest endophenotypic manifestations of bipolar disorder.