Olga A. Averina

Ca²⁺ influx is usually considered a central trigger of neuronal plasticity, especially in mechanisms related to transmitter release and synaptic modification. However, plasticity may also involve mechanisms that do not require Ca²⁺ influx into neurons. We tested whether short-term plasticity can occur in the CA1 region of the mouse hippocampus under Ca²⁺-free conditions. In Ca²⁺-free artificial cerebrospinal fluid, in which synaptic transmission was not detected, local stimulation evoked a population potential in CA1, and theta-burst stimulation led to short-term depression during the stimulation protocol. This depression included three separable components: depression within bursts, cumulative depression of the first response across bursts, and enhancement of within-burst depression during repeated bursts. Whole-cell current-clamp recordings showed that the TBS stimulation protocol also changed action-potential kinetics at the level of individual neurons. These changes were expressed in CA1 pyramidal neurons as a reduction of maximum rise rate and slowing of repolarization, whereas stratum oriens interneurons did not show within-burst depression nor enhancement. Together, these data show that theta-burst stimulation can induce Ca²⁺-influx-independent short-term plasticity of action potentials in hippocampal CA1 pyramidal cells.

Caffeine is the most widely used psychoactive compound. In the brain, caffeine acts as a competitive, non-selective adenosine receptor antagonist of A₁ and A_2A, both known to modulate long-term potentiation (LTP), the cellular basis of learning and memory. But the effects of caffeine on synaptic function and plasticity cannot be reduced to a single inhibitory or facilitatory action. In the CA1 area of the hippocampus, low-micromolar caffeine has been reported to attenuate LTP, yet it remains unclear whether this action extends equally to other plasticity-related responses, including EPSP–spike coupling and paired-pulse responses. Here, we studied the effect of 30 μM caffeine on the field excitatory postsynaptic potentials (fEPSPs) and LTP evoked by Schaffer collateral stimulation in the CA1 region in mouse hippocampal slices. We compared theta-burst-induced long-term fEPSP potentiation, EPSP–spike (E-S) potentiation, input–output relationships, and paired-pulse responses after short (three burst-TBS3) and long (ten burst-TBS10) theta-burst stimulation. Caffeine attenuated long-term fEPSP potentiation induced by the longer theta-burst protocol and reduced the accompanying increase in population spike amplitude. In contrast, E-S potentiation induced by the shorter theta-burst protocol was preserved under caffeine exposure. Input–output analysis further showed that caffeine prevented the increase in population spike amplitude accompanying the development of long-term fEPSP potentiation, but did not prevent the population spike response changes associated with E-S potentiation. Caffeine also reduced paired-pulse deviations from 100%, most clearly for population spike amplitude, and this effect persisted after both the theta-burst protocols. Thus, 30 μM caffeine did not simply suppress CA1 plasticity-related responses, but distinguished TBS10-induced synaptic fEPSP potentiation from TBS3-induced EPSP–spike potentiation. These findings identify EPSP–spike coupling as a caffeine-preserved CA1 plasticity-related response and provide a basis for future receptor-selective and behavioral testing.

BackgroundParkin (PARK2) mutations are among the most common causes of autosomal recessive Parkinson’s disease (PD); however, the phenotypic manifestations of Parkin deficiency in mouse models remain inconsistent.ObjectiveThe aim of this work was to study the effect of the PARK2 gene knockout in mice on the dynamics of behavioral and biochemical parameters of PD.MethodsThe study was performed on C57BL/6-line mice aged from 4 months to 1.5 years: wild type (park2 +/+), heterozygotes (park2 +/-) and homozygotes (park2 -/-) knocked out by the PARK2 using CRISPR-Cas9. The open field test, the Porsolt forced swimming test, the grid-walk test, the beam-walking test, the elevated plus maze test, the accelerating rotarod test were used to assess the behavioral phenotype. Measurement of the concentration of bioamines and their metabolites by HPLC and evaluation of the amount of tyrosine hydroxylase, BDNF and GDNF by Western Blot were used to study the biochemical signs of PD.ResultsPark2 -/- mice begin to show signs of decreased motor activity no earlier than at 4 months of life. At 12 months of life, it was shown only a decrease in the level of the mature isoform of GDNF and an increase in the number of immature isoforms in the frontal cortex and striatum were revealed.ConclusionThese findings indicate that PARK2 knockout mice recapitulate specific functional aspects of Parkinson’s disease while lacking robust neurodegeneration, suggesting their utility as a model of early-stage functional impairment rather than progressive dopaminergic loss.

Caffeine is a widely consumed psychostimulant known to affect memory, yet its dual role in impairing long-term potentiation (LTP) while enhancing cognitive performance remains unresolved. This study aimed to clarify this paradox by investigating the differential effects of caffeine on distinct forms of synaptic plasticity in the hippocampus. Using extracellular recordings in mouse hippocampal slices, we assessed long-term (LTP and E-S potentiation), short-term plasticity, and neuronal excitability under 30 μM caffeine exposure – a physiologically relevant concentration. Our findings confirm that caffeine suppresses LTP but does not inhibit E-S potentiation; instead, it enhances it. Furthermore, caffeine alters excitability in a form-dependent manner, reducing it following LTP and increasing it following E-S potentiation. We also show that caffeine blocks short-term synaptic plasticity regardless of prior LTP induction. These results suggest that E-S potentiation may serve as a caffeine-resistant mechanism for memory formation, potentially mediated by selective modulation of adenosine receptors. This study provides new insight into how caffeine influences synaptic processes underlying learning and memory.

Background: Parkinson’s disease (PD) is a progressive chronic neurodegenerative disease. The PARK2 gene encoding the Parkin protein accounts for approximately half of early-onset autosomal recessive PD cases in humans. Objective: The aim of this work was to study the effect of the PARK2 gene knockout in mice on the dynamics of behavioral and biochemical parameters of PD. Methods: The study was performed on C57BL/6-line mice aged from 4 months to 1.5 years: wild type ( park2 +/+ ), heterozygotes ( park2 +/- ) and homozygotes ( park2 -/- ) knocked out by the PARK2 using CRISPR-Cas9. The open field test, the Porsolt forced swimming test, the grid-walk test, the beam-walking test, the elevated plus maze test, the accelerating rotarod test were used to assess the behavioral phenotype. Measurement of the concentration of bioamines and their metabolites by HPLC and evaluation of the amount of tyrosine hydroxylase, BDNF and GDNF by Western Blot were used to study the biochemical signs of PD. Results: Park2 -/- mice begin to show signs of decreased motor activity no earlier than at 4 months of life. At 12 months of life, it was shown only a decrease in the level of the mature isoform of GDNF and an increase in the number of immature isoforms in the frontal cortex and striatum were revealed. Conclusion: The data obtained indicates a different age dynamic of the condition of mice associated with the PARK2 knockout. However, no pronounced specific manifestations of PD in human were found in park2 -/- mice.

Spermiogenesis requires extensive molecular and structural remodeling to produce motile sperm. Mutations in the testis-specific RNA methyltransferase NSUN7 are associated with defective fibrous sheath, impaired sperm motility, and male infertility. However, the underlying molecular mechanisms remain poorly understood. Here, we performed proteomic profiling of sorted, elongated, and round spermatids, as well as mature spermatozoa from Nsun7 knockout mice. We showed that NSUN7 is present at all stages of spermiogenesis and is most abundant in round spermatids, which corresponds to the formation of the flagellum and fibrous sheath assembly. Loss of NSUN7 altered the abundance of proteins essential for dynein arm assembly (PIH1D3, CCDC103, CCDC40), intraflagellar transport (IFT122), and fibrous sheath organization (AKAP3, AKAP4, ROPN1L). We also showed that the previously detected impaired retention of cytoplasm in elongated spermatids may be caused by plectin accumulation. Interestingly, no statistically significant changes were found in mature sperm proteomes upon Nsun7 inactivation. Our findings support a model in which NSUN7 primarily stabilizes protein complexes and coordinates flagellar assembly. This indicates that NSUN7 is a critical regulator of spermiogenesis, and its malfunction is a contributing factor to male infertility.

Genetic technologies open up opportunities for studying the molecular basis of a wide range of hereditary pathologies, including mental disorders. Modeling certain genomic variants in cellular and animal models allows us to establish their functional significance and potential mechanisms of involvement in the disease progression, as well as lays the material basis for the development and testing of promising drugs. Here, in this study, we created the first line of transgenic mice carrying the P654L (rs139336954) mutation in the Plxna3 nerve tissue morphogenesis protein and studied their cognitive and behavioral characteristics. The Plxna3 protein, together with the Nrp1/Nrp2 co-receptor, detects signals from the repellent molecules Sema3a and Sema3f and determines the direction of cell migration and nerve fiber growth, the processes that are crucial for the proper development of the finely tuned nervous system. According to bioinformatic analysis, this mutation alters the structure of the extracellular domain of Plxna3, which could potentially disrupt the reception of Sema3a and/or Sema3f. Studies of the behavior of mice carrying the Plxna3-P654L (rs139336954) mutation have revealed increased anxiety, a high degree of orderliness, and reduced sensitivity to external stimuli, which could potentially be interpreted as symptoms of obsessive-compulsive personality disorder. No significant macroscopic or histological differences in brain structure were detected between the control and experimental groups. In this study, we draw attention for the first time to the genomic variant rs139336954 in the Plxna3 gene as a potential cause of obsessive-compulsive personality disorder and propose a novel transgenic model organism for studying the pathogenesis of this disease.

Objectives: Oocyte quality is crucial for female fertility, but the underlying molecular mechanisms remain unclear. This study investigates the non-canonical role of the telomerase RNA protein (TERP), whose function in oogenesis is unknown, in safeguarding female gamete quality. Methods: We used gain-of-function (AT) and loss-of-function (D7) mutant mouse lines to assess oocyte quality via morphological and molecular analyses. Key methods included immunofluorescence of meiotic spindles, Western blotting for the autophagy marker LC3B, and qRT-PCR to quantify the perinatal ovarian reserve. Results: Both AT and D7 mutations caused severe meiotic spindle abnormalities, including aberrant morphology and increased size. The D7 mutation, in particular, led to impaired cytoplasmic maturation and reduced autophagy levels in oocytes. Furthermore, loss of TERP function resulted in an abnormally large ovarian reserve in newborn females, which correlated with decreased expression of autophagy and lysosomal markers in the newborn ovary. Conclusions: This study establishes a novel, non-canonical function for TERP as a crucial regulator of oocyte quality. TERP dysregulation compromises meiotic integrity and oocyte maturation by disrupting lysosome-dependent autophagy.

Neurotrophic factors and guidance molecules are key regulators of the processes of brain formation, growth and maturation. During early stages of embryogenesis, they stimulate proliferation and differentiation of neural progenitors, direct their migration, and promote the establishment and maintenance of interneuronal connections. Timely expression and correct functioning of multiple molecules, primarily neurotrophic factors, guidance molecules and their receptorsprovide the high coordination of these processes. And this makes it possible to form the brain as an integral structure and lay the basis for its cognitive and mental activity during a short period of prenatal development. On the contrary, aberrant activity or stoichiometry of such molecules, spatial or temporal impairment of their expression, can disrupt the formation of distinct brain structures or their adequate interaction and lay a redisposition to a number of psychiatric and neurological disorders such as schizophrenia, bipolar disorder, autism, obsessive-compulsive disorder, attention deficit hyperactivity disorder, epilepsy and others. This is confirmed by a number of clinical observations, animal studies and in vitro models. Despite the obvious contribution of brain ontogenesis onto the development of psycho-cognitive features of personality and the formation of predisposition to mental diseases, very little attention is paid to study ofbrain ontogenesis and molecules involved within this context. Apparently, it is difficult to identify the morphogenetic molecules and signaling cascades involved in due to the complexity of brain ontogenesis and the polygenic nature of mental disorders. All this restricts our understanding of the etiology and pathogenesis of mental disorders and does not allow their timely diagnosis and prevention. The aim of this review is to summarize the known facts about the possible role of neurotrophic and guidance molecules in the processes of brain development and pathogenesis of a number of mental disorders, and to emphasize the need for more research in this area of molecular psychiatry.