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Heterosynaptic plasticity, along with Hebbian homosynaptic plasticity, is an important mechanism ensuring the stable operation of learning neuronal networks. However, whether heterosynaptic plasticity occurs in the whole brain in vivo, and what role(s) in brain function in vivo it could play, remains unclear. Here, we used an optogenetics approach to apply a model of intracellular tetanization, which was established and employed to study heterosynaptic plasticity in brain slices, to study the plasticity of response properties of neurons in the mouse visual cortex in vivo. We show that optogenetically evoked high-frequency bursts of action potentials (optogenetic tetanization) in the principal neurons of the visual cortex induce long-term changes in the responses to visual stimuli. Optogenetic tetanization had distinct effects on responses to different stimuli, as follows: responses to optimal and orthogonal orientations decreased, responses to null direction did not change, and responses to oblique orientations increased. As a result, direction selectivity of the neurons decreased and orientation tuning became broader. Since optogenetic tetanization was a postsynaptic protocol, applied in the absence of sensory stimulation, and, thus, without association of presynaptic activity with bursts of action potentials, the observed changes were mediated by mechanisms of heterosynaptic plasticity. We conclude that heterosynaptic plasticity can be induced in vivo and propose that it may play important homeostatic roles in operation of neural networks by helping to prevent runaway dynamics of responses to visual stimuli and to keep the tuning of neuronal responses within the range optimized for the encoding of multiple features in population activity.

Gene therapy offers a potential alternative to the surgical treatment of epilepsy, which affects millions of people and is pharmacoresistant in ~30% of cases. Aimed at reducing the excitability of principal neurons, the engineered expression of K + channels has been proposed as a treatment due to the outstanding ability of K + channels to hyperpolarize neurons. However, the effects of K + channel overexpression on cell physiology remain to be investigated. Here we report an adeno-associated virus (AAV) vector designed to reduce epileptiform activity specifically in excitatory pyramidal neurons by expressing the human Ca 2+ -gated K + channel KCNN4 (KCa3.1). Electrophysiological and pharmacological experiments in acute brain slices showed that KCNN4-transduced cells exhibited a Ca 2+ -dependent slow afterhyperpolarization that significantly decreased the ability of KCNN4-positive neurons to generate high-frequency spike trains without affecting their lower-frequency coding ability and action potential shapes. Antiepileptic activity tests showed potent suppression of pharmacologically induced seizures in vitro at both single cell and local field potential levels with decreased spiking during ictal discharges. Taken together, our findings strongly suggest that the AAV-based expression of the KCNN4 channel in excitatory neurons is a promising therapeutic intervention as gene therapy for epilepsy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Spreading depolarization (SD), underlying mechanism of migraine aura and potential activator of pain pathways, is known to elicit transient local silencing cortical activity. Sweeping across the cortex, the electrocorticographic depression is supposed to underlie spreading negative symptoms of migraine aura. Main information about the suppressive effect of SD on cortical oscillations was obtained in anesthetized animals while ictal recordings in conscious patients failed to detect EEG depression during migraine aura. Here, we investigate the suppressive effect of SD on spontaneous cortical activity in awake animals and examine whether the anesthesia modifies the SD effect., Methods: Spectral and spatiotemporal characteristics of spontaneous cortical activity following a single unilateral SD elicited by amygdala pinprick were analyzed in awake freely behaving rats and after induction of urethane anesthesia., Results: In wakefulness, SD transiently suppressed cortical oscillations in all frequency bands except delta. Slow delta activity did not decline its power during SD and even increased it afterwards; high-frequency gamma oscillations showed the strongest and longest depression under awake conditions. Unexpectedly, gamma power reduced not only during SD invasion the recording cortical sites but also when SD occupied distant subcortical/cortical areas. Contralateral cortex not invaded by SD also showed transient depression of gamma activity in awake animals. Introduction of general anesthesia modified the pattern of SD-induced depression: SD evoked the strongest cessation of slow delta activity, milder suppression of fast oscillations and no distant changes in gamma activity., Conclusion: Slow and fast cortical oscillations differ in their vulnerability to SD influence, especially in wakefulness. In the conscious brain, SD produces stronger and spatially broader depression of fast cortical oscillations than slow ones. The frequency-specific effects of SD on cortical activity of awake brain may underlie some previously unexplained clinical features of migraine aura., (© 2024. The Author(s).)

Cortical spreading depolarization (CSD) is the neuronal correlate of migraine aura and the reliable consequence of acute brain injury. The role of CSD in triggering headaches that follow migraine aura and brain injury remains to be uncertain. We examined whether a single CSD occurring in awake animals modified the expression of proinflammatory cytokines (Il1b, TNF, and Il6) and endogenous mediators of nociception/neuroinflammation-pannexin 1 (Panx1) channel and calcitonin gene-related peptide (CGRP), transforming growth factor beta (TGFb) in the cortex. Unilateral microinjury of the somatosensory cortex triggering a single CSD was produced in awake Wistar rats. Three hours later, tissue samples from the lesioned cortex, intact ipsilesional cortex invaded by CSD, and homologous areas of the contralateral sham-treated cortex were harvested and analyzed using qPCR. Three hours post-injury, intact CSD-exposed cortexes increased TNF, Il1b, Panx1, and CGRP mRNA levels. The strongest upregulation of proinflammatory cytokines was observed at the injury site, while CGRP and Panx1 were upregulated more strongly in the intact cortexes invaded by CSD. A single CSD is sufficient to produce low-grade parenchymal neuroinflammation with simultaneous overexpression of Panx1 and CGRP. The CSD-induced molecular changes may contribute to pathogenic mechanisms of migraine pain and post-injury headache.

Spreading depolarization (SD), a self-propagated wave of transient depolarization, regularly occurs in the cortex after acute brain insults and is now referred as an important diagnostic and therapeutic target in patients with acute brain injury. Here, we show that the amygdala, the limbic structure responsible for post-injury neuropsychological symptoms, exhibits strong regional heterogeneity in vulnerability to SD with high susceptibility of its basolateral (BLA) region and resilience of its centromedial (CMA) region to triggering SD by acute focal damage. The BLA micro-injury elicited SD twice as often compared with identical injury of the CMA region (71% vs. 33%). Spatiotemporal features of SDs triggered in the amygdala indicated diverse patterns of the SD propagation to the cortex. Our results suggest that even relatively small cerebral structures can exhibit regional gradients in their susceptibility to SD and the heterogeneity may contribute to the generation of complex SD patterns in the injured brain.

Proline-rich antimicrobial peptides (PR-AMPs) having a potent antimicrobial activity predominantly toward Gram-negative bacteria and negligible toxicity toward host cells, are attracting attention as new templates for developing antibiotic drugs. We have previously isolated and characterized several bactenecins that are promising in this respect, from the leukocytes of the domestic goat Capra hircus : ChBac5, miniChBac7.5N-α, and -β, as well as ChBac3.4. Unlike the others, ChBac3.4 shows a somewhat unusual pattern of activities for a mammalian PR-AMP: it is more active against bacterial membranes as well as tumor and, to the lesser extent, normal cells. Here we describe a SAR study of ChBac3.4 (RFRLPFRRPPIRIHPPPFYPPFRRFL-NH2) which elucidates its peculiarities and evaluates its potential as a lead for antimicrobial or anticancer drugs based on this peptide. A set of designed structural analogues of ChBac3.4 was explored for antibacterial activity toward drug-resistant clinical isolates and antitumor properties. The N -terminal region was found to be important for the antimicrobial action, but not responsible for the toxicity toward mammalian cells. A shortened variant with the best selectivity index toward bacteria demonstrated a pronounced synergy in combination with antibiotics against Gram-negative strains, albeit with a somewhat reduced ability to inhibit biofilm formation compared to native peptide. C -terminal amidation was examined for some analogues, which did not affect antimicrobial activity, but somewhat altered the cytotoxicity toward host cells. Interestingly, non-amidated peptides showed a slight delay in their impact on bacterial membrane integrity. Peptides with enhanced hydrophobicity showed increased toxicity, but in most cases their selectivity toward tumor cells also improved. While most analogues lacked hemolytic properties, a ChBac3.4 variant with two additional tryptophan residues demonstrated an appreciable activity toward human erythrocytes. The variant demonstrating the best tumor/nontumor cell selectivity was found to more actively initiate apoptosis in target cells, though its action was slower than that of the native ChBac3.4. Its antitumor effectiveness was successfully verified in vivo in a murine Ehrlich ascites carcinoma model. The obtained results demonstrate the potential of structural modification to manage caprine bactenecins' selectivity and activity spectrum and confirm that they are promising prototypes for antimicrobial and anticancer drugs design., (Copyright © 2020 Kopeikin, Zharkova, Kolobov, Smirnova, Sukhareva, Umnyakova, Kokryakov, Orlov, Milman, Balandin, Panteleev, Ovchinnikova, Komlev, Tossi and Shamova.)

To create a broad-spectrum peptide biocide, we synthesized 45 analogs of antimicrobial peptide indolicidin (H-Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg-NH 2 ). Among them the peptides H-Ile-Leu-Pro-(2-Me)Phe-Lys-(2-Me)Phe-Pro-(2-Me)Phe-(2-Me)Phe-Pro-(2-Me)Phe-Arg-Arg-NH 2 and HN 2 -(CH 2 ) 10 -Ile-Leu-Pro-D-Phe-Lys-D-Phe-Pro-D-Phe-D-Phe-Pro-D-Phe-Arg-Arg-NH 2 have the broadest spectrum of antimicrobial activity and the lowest hemolytic activity. They are active against all 11 tested strains of Gram-positive bacteria, Gram-negative bacteria and fungi with MIC 50 from 0.9 to 6.1 μg/ml (0.5 to 3.2 μM), being up to 3 times more active than indolicidin, and are at least 1.8 times less hemolytically active than indolicidin (reached the detection limit). These peptides are patented and could be used for further drug development as antimicrobials., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Natural peptides with antimicrobial activity are extremely diverse, and peptide synthesis technologies make it possible to significantly improve their properties for specific tasks. Here, we investigate the biological properties of the natural peptide indolicidin and the indolicidin-derived novel synthetic peptide In-58. In-58 was generated by replacing all tryptophan residues on phenylalanine in D-configuration; the α-amino group in the main chain also was modified by unsaturated fatty acid. Compared with indolicidin, In-58 is more bactericidal, more resistant to proteinase K, and less toxic to mammalian cells. Using molecular physics approaches, we characterized the action of In-58 on bacterial cells at the cellular level. Also, we have found that studied peptides damage bacterial membranes. Using the Escherichia coli luminescent biosensor strain MG1655 (pcolD'::lux), we investigated the action of indolicidin and In-58 at the subcellular level. At subinhibitory concentrations, indolicidin and In-58 induced an SOS response. Our data suggest that indolicidin damages the DNA, but bacterial membrane perturbation is its principal mode of action. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd., (Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.)

Patients with heart connective tissue dysplasia (HCTD) are known to be subject to infectious and inflammatory diseases due to peculiarities of their immune system. We studied 181 patients with HCTD depending on thyroid hormone levels and vegetative dysfunction. HCTD was shown to be associated with a significant decrease of IgM levels and increase of circulating immune complexes. The IgG level in patients with mitral valve prolapse (MVP), anomalous chord localization, and combination of MPV and tricuspid valve prolapse was significantly higher than in the absence of HCTD. Patients with and without HCTD showed the dependence of IgA levels on TSH concentration. In those with combined MPV the intensity of chemiluminescence was related to the T4 level. The dependence of IgM levels on he presence ofvegetative dysfunction was documented in patients with MVP.

We studied the effect of vasopressin analogue desglycinamide-arginine-vasopressin on changes in platelet hemostasis produced by intragastric administration of Ticlid or clopidogrel (inhibitors of ADP-induced platelet aggregation). Intranasal administration of the peptide under conditions of hemorrhagic diathesis produced a hemostatic effect and normalized some parameters of blood coagulation.

The antibacterial peptide indolicidin and a number of its analogues were obtained by solid phase synthesis. An optimized method of the synthesis using the Boc strategy was suggested. It was shown that the therapeutic index of indolicidin analogues increased with a decrease in the total positive charge of the molecule and its amphipathicity; i.e., the hemolytic activity of analogues within the range of concentrations examined was practically absent, while the antibacterial activity was preserved. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 5; see also http: // www.maik.ru.

Neuropeptide galanin produces a antipyretic effect in experimental pyrogenic reaction induced by intraperitoneal injection of lipopolysaccharide. Central intracerebroventricular injection of 100 ng galanin significantly attenuated, but did not completely abolish fever. Central galanin injection potentiated endotoxin-induced activation of the noradrenergic system and blocked activation of the serotoninergic system of the anterior hypothalamus.

In this work polyfunctional peripheral (pancreas) and central effects of galanin 1-29 (gal.) were reviewed. In hypothalamus gal. exerts neuroendocrine effects through modulation of secretion of principal hormones of hypophysis, co-localized with acetylcholine in some brain structures including hippocampus. Gal. influences behaviour and memory. Newest hypotheses of T. Hokfelt and J. N. Crawely [correction of G. Crowly] on the involvement of gal. to pathogenesis of in Alzheimer disease and possibilities of its clinical antiamnestic utility are discussed. Our own data indicates antiseizure effect of gal. in the model of febrile convulsions in children--hyperthermia induced seizures in neonatal rats in the age from 5 to 13 days. Systemic intraperitoneal administration of gal. was effective in certain age--7-11 days of postnatal period--in preventing hyperthermia induced seizures: in increased by 2-3 times latency of minimal seizures and clonic-tonic generalized seizures. In adults rats gal. showed antiseizure action when administered intranasal in the model of pentilenetetrazol seizures (modified test with repeated administration of subthreshold doses). Modern data on structure and function of galanin, its chimeric analogs and galanin receptors receptors are discussed.

The effect of modified forms of vasopressin (MFV) that do not possess hormonal activity on homeostasis in rats was studied. One of the major effects of vasopressin (AVP) and its analogs on the blood clotting system, changes in fibrinolytic activity (FA) and the activity of plasminogen activator (APA), depends on modifications of the amino acid sequence in the peptide molecule. The presence of glycinamide in the AVP molecule enhances FA and APA. AVP molecules without the glycinamide group exert a more marked influence on procoagulant activity in blood.

L-lysine-alpha-oxidase from Trichoderma sp. fungi inhibits the synthesis of DNA, RNA and protein in cultivated cells of the Burkitt lymphoma (strain P3HRj) in vitro, which results in the blocking of the cells' transfer from phase S to phase G2/M of the mitotic cycle.

The data on the study of various soils and substrates for isolation of Micromonospora from them are presented. It was shown that Micromonospora predominated in moist soils and especially in such substrates as silts where their content with respect to the all actinomycetous isolates amounted to 88.9 per cent. In the silts the content of Micromonospora amounted to 66.6--83 per cent, in the sopromely its content was 66 per cent, while in the ordinary non-moist soil its content was from 6 to 11 per cent. Predominance of Micromonospora in silts and moist soils makes its directed search possible.