Inhibition of ERK1/2 signaling prevents epileptiform behavior in rats prone to audiogenic seizures

It has recently been proposed that extracellular signal‐regulated kinases 1 and 2 (ERK1/2) are one of the factors mediating seizure development. We hypothesized that inhibition of ERK1/2 activity could prevent audiogenic seizures by altering GABA and glutamate release mechanisms. Krushinsky–Molodkina rats, genetically prone to audiogenic seizure, were recruited in the experiments. Animals were i.p. injected with an inhibitor of ERK1/2 SL 327 at different doses 60 min before audio stimulation. We demonstrated for the first time that inhibition of ERK1/2 activity by SL 327 injections prevented seizure behavior and this effect was dose‐dependent and correlated with ERK1/2 activity. The obtained data also demonstrated unchanged levels of GABA production, and an increase in the level of vesicular glutamate transporter 2. The study of exocytosis protein expression showed that SL 327 treatment leads to downregulation of vesicle‐associated membrane protein 2 and synapsin I, and accumulation of synaptosomal‐associated protein 25 (SNAP‐25). The obtained data indicate that the inhibition of ERK1/2 blocks seizure behavior presumably by altering the exocytosis machinery, and identifies ERK1/2 as a potential target for the development of new strategies for seizure treatment.

     

Effect of Block of Catecholamine Synthesis on the Functional State of Vasopressinergic Neurons of Hypothalamus in Dehydrated Rats

Effect of catecholamines (CA) on the functional state of vasopressin (VP)-ergic neurons of hypothalamus at their stimulation produced by dehydration (salt diet and water deprivation) was studied in in vivo experiments on adult male Wistar rats. Quantitative assessment of VP-immunopositive substance and digoxigenin-labeled VP mRNA (hybridization in situ) in neurosecretory cells of supraoptic (SON) and paraventricular (PVN) nuclei was performed using measurements of optical density of the stained substance in perykaria and a computer digital television analyzer with PhotoM software. Hybridization in situ technique allowed evaluating intensity of VP synthesis, while comparison of the amount of VP mRNA and VP-immunoreactive substance in neurons of SON and PVN made it possible to evaluate release of VP from perykaria. In PVN, repeated saline administration (0.25 ml per 100 g weight) and severe dehydration led to activation both of synthesis and of release of VP from cell perikarya. Use of -methyl-p-tyrosine, an inhibitor of catecholamine (CA) synthesis on the background of dehydration was not accompanied by changes of the functional state of VP-ergic neurons of PVN as compared with dehydrated animals. No changes in functional state of VP-ergic neurosecretory cells in SON were found after saline administration, whereas dehydration activated synthesis and release of VP from perykaria, like in VP-ergic neurons of PVN. Inhibition of CA synthesis on the background of dehydration led to activation of VP release by SON neurons without affecting the level of VP synthesis. The data obtained indicate that CA is able to suppress the VP release from neurons of SON, which is produced caused by activation of the VP-ergic system under conditions of dehydration.     

Hemispheric Asymmetry in Prosody Perception by Healthy Subjects and Schizophrenic Patients

The interhemispheric interactions in perception of Russian prosody were studied in the norm and in schizophrenia as a clinical model of impaired hemispheric interactions. Monaural presentation of stimuli and binaural presentation in a free acoustical field were used. Sentences with main variants of Russian prosodic intonations were used as stimuli. The response time and the number of erroneous responses were recorded. In binaural listening without headphones, no significant difference in the percent of errors in identifying the emotional prosody was found between healthy subjects and schizophrenics. Compared with the healthy subjects, the patients made more errors in understanding the logical stress and fewer errors in understanding the syntagmatic segmentation. By response time, a significant dominance of the left ear was revealed in the healthy subjects during monaural listening to sentences with emotional prosody and complete or incomplete sentences, whereas no significant ear dominance was found in the schizophrenics. During monaural listening to sentences with logical stress, the response time was shorter when stimuli were presented to the right ear both in the healthy subjects and in the schizophrenics. The results testified that the functional brain asymmetry in schizophrenics is flattened. The flattening was less evident in the perception of a logical stress in a sentence and did not significantly affect the efficiency of identification of emotional prosody and syntagmatic segmentation of a sentence.     

Analysis of ERK1/2 kinases in the inferior colliculus of rats genetically prone to audiogenic seizures during postnatal development

The activity of ERK1/2 kinases in the quadrigemina inferior colliculus of Krushinsky–Molodkina rats of different age, which are characterized by an increased seizure readiness compared to Wistar rats, was analyzed. An increased (probably genetically determined) activity of these enzymes during the development of epileptiform activity in ontogeny was found, which may be the cause of abnormalities in the neurotransmitter system functioning.     

Specialization of cerebral hemispheres in the perception of Russian intonations

Relations between the brain hemispheres were studied during the human perception of various types of Russian intonations. Fifty healthy subjects with normal hearing took part in the tests based on the method of monaural presentation of stimuli—the sentences that represented the main kinds of Russian emotional and linguistic intonations. The linguistic intonations expressed: various communicative types of sentences; completeness/incompleteness of a statement; various types of the syntagmatic segmentation of the statements; various logical stress. Sentences that required the identification of the emotion quality were used to study the perception of emotional intonations. The results of statistical analysis of latent periods and errors made by the test subjects demonstrated a significant preference of theright hemisphere in perceiving emotional intonations and complete/incomplete sentences; sentences with different logical stress were perceived mainly by theleft hemisphere. No significant differences were found in the perception of various communicative types of sentences and statements with different syntagmatic segmentation. The obtained data also testify to a difference in the degree of the involvement of human hemispheres in the perception and analysis of prosodic characteristics of the speech in males and females.     

Interaction of neuronal NOS and catecholamines in regulation of expression of proteins of apoptosis by vasopressinergic hypothalamic neurons

The work deals with studies on vasopressinergic neurons of hypothalamic supraoptic and paravenricular nuclei in the wild type mice and the neuronal nitric oxide synthase (nNOS) in the gene knockouted mice at a decrease of the brain catecholamine (CA) level caused by administration of the blocker of activity of tyrosine hydroxylase α-methyl-paratyrosine (α-MPT) and at the CA level decrease on the background of functional activity of the vasopressinergic neurons caused by dehydration of animals. There were analyzed changes in the number of neurons in the magnocellular hypothalamic nuclei expressing proapoptotic proteins caspase-8 and caspase-9, p53, and antiapoptotic protein Bcl-2. Disturbance of the CAergic innervation was shown to be a strong damaging factor leading to apoptosis of neurons regardless of the presence of nNOS in the cells. However, at disturbance of the CAergic innervation due to the 5-day mouse dehydration, no death of neurons by apoptosis was revealed. Thus, it is possible that functional activation prevents the hypothalamic vasopressinergic neurons from death at a decrease of the CA level in brain. The main difference of the nNOS gene knockouts is the absence of activation of the Bcl-2 expression under all used actions. This confirms our suggestion about interaction of CA and NO in triggering of expression of the antiapoptotic protein Bcl-2.     

A PET Study of the Brain Mechanisms Underlying Perception of Phrases with Syntagmatic Splitting

Positron emission tomography (PET) was used to localize the brain regions involved in the processing of pauses and intonation changes, which underlie the syntactically correct perception of auditory verbal stimuli. Subjects were asked to listen to a phrase and to choose a correct answer from two variants presented on a monitor screen. Differences in cerebral blood circulation were mapped for perception of phrases containing or lacking a pause determining the meaning. Conscious analysis of the phrase structure was associated with activation of the right lower prefrontal area and the right posterior medial area of the cerebellum. The possible role of these brain structures in analyzing factors of syntagmatic splitting is discussed.