The nigrostriatal system composed of the dorsal striatum and the substantia nigra (SN) is highly involved in the control of motor behavior. Various extremal and pathological conditions as well as social isolation may cause an impairment of locomotor function; however, corresponding alterations in the nigrostriatal dopaminergic pathway are far from full understanding. Here we analyzed the effect of 3-day hindlimb unloading (HU) and social isolation (SI) on the key players of dopamine transmission in the nigrostriatal system of CD1 mice. Three groups of mice were analyzed: group-housed (GH), SI, and HU. Our data showed a significant decrease in the expression of tyrosine hydroxylase (TH) in the SN and dorsal striatum of HU mice, but only in comparison with SI group that suggested attenuation of dopamine synthesis in response to HU, while TH phosphorylation was reduced in comparison with both GH and SI animals. SI also led to a decrease in TH phosphorylation in the dorsal striatum that pointed on an impact of isolation too. Expression of dopamine receptors D1 in the dorsal striatum of HU mice was increased suggesting a compensatory response, but the activity of downstream signaling pathways involving PKA and CREB was inhibited. But in the dorsal striatum of SI mice, expression of DA receptors and activity of downstream signaling was not affected. Obtained data let us to conclude that combination of short-term HU and isolation impaired dopamine transmission in the nigrostriatal system.

Epilepsy is associated with aberrant neurogenesis in the hippocampus and may underlie the development of hereditary epilepsy. In the present study, we analyzed the differentiation fate of neural progenitor cells (NPC), which were isolated from the hippocampus of embryos of Krushinsky-Molodkina (KM) rats genetically prone to audiogenic epilepsy. NPCs from embryos of Wistar rats were used as the control. We found principal differences between Wistar and KM NPC in unstimulated controls: Wistar NPC culture contained both gamma-aminobutyric acid (GABA) and glutamatergic neurons; KM NPC culture was mainly represented by glutamatergic cells. The stimulation of glutamatergic differentiation of Wistar NPC resulted in a significant increase in glutamatergic cell number that was accompanied by the activation of protein kinase A. The stimulation of KM NPC led to a decrease in immature glutamatergic cell number and was associated with the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B/ glycogen synthase kinase 3 beta (Akt/GSK3β), which indicates the activation of glutamatergic cell maturation. These results suggest genetically programmed abnormalities in KM rats that determine the glutamatergic fate of NPC and contribute to the development of audiogenic epilepsy.

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