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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.

Abstract 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.

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.