Functional state of the nigrostriatal system of Krushinsky–Molodkina rats during audiogenic seizure expression

Neurochemical mechanisms of initiation and expression of epileptic seizures are pure explored, and there is no published data that could demonstrate a functional state of the neuromediator systems at the initial state of seizure in the animals genetically prone to seizure. In the current work we studied the role of extracellular signal-regulated kinase (ERK1/2) in the regulation of the nigrostriatal glutamate, GABA and dopamine neurons of Krushinsky–Molodkina rats at clonus-tonus and ataxia stages of audiogenic seizure. We demonstrated upregulation of ERK1/2 activity upon audio stimulation that was accompanied with increased activation of Synapsin I in the striatum and substantia nigra in comparison to intact Krushinsky–Molodkina rats. The observed exocytosis activation led to secretion of glutamate in the striatum and as a result to stimulation of seizures. However, at clonus-tonus stage in the striatum we revealed the changes that could participate in further inhibition of the seizure activity, such as increased phosphorylation of tyrosine hydroxylase upon increased ERK1/2 activity followed by activation of dopamine release in the pars compacta of the substantia nigra. At the same time it was observed enhanced D2 and increased D1 dopamine receptor contents. These data revealed attenuation of direct (pro-seizure) and indirect (anti-seizure) pathways of the regulation of the substantia nigra GABA neurons. We demonstrated activation of GABA in the substantia nigra pars reticulata that probably resulted in the inhibition of glutamate neurons of the thalamus that could be one of the mechanisms the initiations of ataxia.