Volodymyr Krotov

Bogomoletz Institute of Physiology

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Nana Voitenko

Kyiv Academic University

Olga Kopach

University College London

Pavel Belan

Bogomoletz Institute of Physiology

Kirill Agashkov

Bogomoletz Institute of Physiology

Boris V. Safronov

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto

КА

К А Садоха

Belarusian Medical Academy of Post-Graduate Education

Oksana Rybachuk

Institute of Genetic and Regenerative Medicine of the National Academy of Medical Sciences of Ukraine

Marharyta Krasniakova

Bogomoletz Institute of Physiology

Ian D. Coombs

University College London

Julie Ziobro

University of Michigan–Ann Arbor

Cooperative Institutions

Bogomoletz Institute of Physiology

University of California, San Diego

National Academy of Sciences of Ukraine

Institute of Molecular Biology and Genetics

Czech Academy of Sciences

National Academy of Medical Sciences of Ukraine

Bogomolets National Medical University

University College London

Romodanov Neurosurgery Institute of the National Academy of Medical Sciences of Ukraine

Charles University

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ШЕЙНАЯ КОМПРЕССИОННАЯ РАДИКУЛОПАТИЯ

Медицинские новости (2019)

К А Садоха А М Головко Volodymyr Krotov

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A gain‐of‐function GRIA2 variant associated with neurodevelopmental delay and seizures: Functional characterization and targeted treatment

Epilepsia (2022)

Ian D. Coombs Julie Ziobro Volodymyr Krotov Taryn‐Leigh Surtees Stuart Cull-Candy

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) are ligand-gated cationic channels formed from combinations of GluA1-4 subunits. Pathogenic variants of GRIA1-4 have been described in patients with developmental delay, intellectual disability, autism spectrum disorder, and seizures, with GRIA2 variants typically causing AMPAR loss of function. Here, we identify a novel, heterozygous de novo pathogenic missense mutation in GRIA2 (c.1928 C>T, p.A643V, NM_001083619.1) in a 1-year-old boy with epilepsy, developmental delay, and failure to thrive. We made patch-clamp recordings to compare the functional and pharmacological properties of variant and wild-type receptors expressed in HEK293 cells, with and without the transmembrane AMPAR regulatory protein γ2. This showed GluA2 A643V-containing AMPARs to exhibit a novel gain of function, with greatly slowed deactivation, markedly reduced desensitization, and increased glutamate sensitivity. Perampanel, an antiseizure AMPAR negative allosteric modulator, was able to fully block GluA2 A643V/γ2 currents, suggesting potential therapeutic efficacy. The subsequent introduction of perampanel to the patient's treatment regimen was associated with a marked reduction in seizure burden, a resolution of failure to thrive, and clear developmental gains. Our study reveals that GRIA2 disorder can be caused by a gain-of-function variant, and both predicts and suggests the therapeutic efficacy of perampanel. Perampanel may prove beneficial for patients with other gain-of-function GRIA variants.

10.1111/epi.17419

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Functional Characterization of Lamina X Neurons in ex-Vivo Spinal Cord Preparation

Frontiers in Cellular Neuroscience (2017)

Volodymyr Krotov Anastasia Tokhtamysh Olga Kopach Andrew Dromaretsky Yevhenii Sheremet

Functional properties of lamina X neurons in the spinal cord remain unknown despite the established role of this area for somatosensory integration, visceral nociception, autonomic regulation and motoneuron output modulation. Investigations of neuronal functioning in the lamina X have been hampered by technical challenges. Here we introduce an ex-vivo spinal cord preparation with both dorsal and ventral roots still attached for functional studies of the lamina X neurons and their connectivity using an oblique LED illumination for resolved visualization of lamina X neurons in a thick tissue. With the elaborated approach, we demonstrate electrophysiological characteristics of lamina X neurons by their membrane properties, firing pattern discharge and fiber innervation (either afferent or efferent). The tissue preparation has been also probed using Ca2+ imaging with fluorescent Ca2+ dyes (membrane-impermeable or -permeable) to demonstrate the depolarization-induced changes in intracellular calcium concentration in lamina X neurons. Finally, we performed visualization of subpopulations of lamina X neurons stained by retrograde labeling with aminostilbamidine dye to identify sympathetic preganglionic and projection neurons in the lamina X. Thus, the elaborated approach provides a reliable tool for investigation of functional properties and connectivity in specific neuronal subpopulations, boosting research of lamina X of the spinal cord.

Lamina

Ex vivo

10.3389/fncel.2017.00342

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Elucidating afferent-driven presynaptic inhibition of primary afferent input to spinal laminae I and X

Frontiers in Cellular Neuroscience (2023)

Volodymyr Krotov Kirill Agashkov Sergii Romanenko Oleh Halaidych Yaroslav Andrianov

Although spinal processing of sensory information greatly relies on afferent-driven (AD) presynaptic inhibition (PI), our knowledge about how it shapes peripheral input to different types of nociceptive neurons remains insufficient. Here we examined the AD-PI of primary afferent input to spinal neurons in the marginal layer, lamina I, and the layer surrounding the central canal, lamina X; two nociceptive-processing regions with similar patterns of direct supply by Aδ- and C-afferents. Unmyelinated C-fibers were selectively activated by electrical stimuli of negative polarity that induced an anodal block of myelinated Aβ/δ-fibers. Combining this approach with the patch-clamp recording in an ex vivo spinal cord preparation, we found that attenuation of the AD-PI by the anodal block of Aβ/δ-fibers resulted in the appearance of new mono- and polysynaptic C-fiber-mediated excitatory postsynaptic current (EPSC) components. Such homosegmental Aβ/δ-AD-PI affected neurons in the segment of the dorsal root entrance as well as in the adjacent rostral segment. In their turn, C-fibers from the L5 dorsal root induced heterosegmental AD-PI of the inputs from the L4 Aδ- and C-afferents to the neurons in the L4 segment. The heterosegmental C-AD-PI was reciprocal since the L4 C-afferents inhibited the L5 Aδ- and C-fiber inputs, as well as some direct L5 Aβ-fiber inputs. Moreover, the C-AD-PI was found to control the spike discharge in spinal neurons. Given that the homosegmental Aβ/δ-AD-PI and heterosegmental C-AD-PI affected a substantial percentage of lamina I and X neurons, we suggest that these basic mechanisms are important for shaping primary afferent input to the neurons in the spinal nociceptive-processing network.

Nociceptor

10.3389/fncel.2022.1029799

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Optimized Model of Cerebral Ischemia In situ for the Long-Lasting Assessment of Hippocampal Cell Death

Frontiers in Neuroscience (2017)

Oksana Rybachuk Olga Kopach Volodymyr Krotov Nana Voitenko Tatyana Pivneva

Among all the brain, the hippocampus is the most susceptible region to ischemic lesion, with the highest vulnerability of CA1 pyramidal neurons to ischemic damage. This damage may cause either prompt neuronal death (within hours) or with a delayed appearance (over days), providing a window for applying potential therapies to reduce or prevent ischemic impairments. However, the time course when ischemic damage turns to neuronal death strictly depends on experimental modelling of cerebral ischemia and, up to now, studies were predominantly focused on a short time-window ¬– from hours to up to a few days post-lesion. Using different schemes of oxygen-glucose deprivation (OGD), the conditions taking place upon cerebral ischemia, we optimized a model of mimicking ischemic conditions in organotypical hippocampal slices for the long-lasting assessment of CA1 neuronal death (at least three weeks). By combining morphology and electrophysiology, we show that prolonged (30-min duration) OGD results in a massive neuronal death and overwhelmed astrogliosis within a week post-OGD whereas OGD of a shorter duration (10-min) triggered programmed CA1 neuronal death with a significant delay – within 2 weeks – accompanied with drastically impaired CA1 neuron functions. Our results provide a rationale towards optimized modelling of cerebral ischemia for reliable examination of potential treatments for brain neuroprotection, neuro-regeneration or testing neuroprotective compounds in situ.

10.3389/fnins.2017.00388

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Opposite, bidirectional shifts in excitation and inhibition in specific types of dorsal horn interneurons are associated with spasticity and pain post-SCI

Scientific Reports (2017)

Olga Kopach Volodymyr Мedvediev Volodymyr Krotov Anya L. Borisyuk Vitaliy Tsymbaliuk

Spasticity, a common complication after spinal cord injury (SCI), is frequently accompanied by chronic pain. The physiological origin of this pain (critical to its treatment) remains unknown, although spastic motor dysfunction has been related to the hyperexcitability of motoneurons and to changes in spinal sensory processing. Here we show that the pain mechanism involves changes in sensory circuits of the dorsal horn (DH) where nociceptive inputs integrate for pain processing. Spasticity is associated with the DH hyperexcitability resulting from an increase in excitation and disinhibition occurring in two respective types of sensory interneurons. In the tonic-firing inhibitory lamina II interneurons, glutamatergic drive was reduced while glycinergic inhibition was potentiated. In contrast, excitatory drive was boosted to the adapting-firing excitatory lamina II interneurons while GABAergic and glycinergic inhibition were reduced. Thus, increased activity of excitatory DH interneurons coupled with the reduced excitability of inhibitory DH interneurons post-SCI could provide a neurophysiological mechanism of central sensitization and chronic pain associated with spasticity.

Interneuron

Disinhibition

10.1038/s41598-017-06049-7

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Проблемы вертеброневрологии: история вопроса и современный этап развития (обзор литературы)

Неврология и нейрохирургия Восточная Европа (2024)

К А Садоха В.И. Курмашев Volodymyr Krotov В.А. Пасичниченко

В статье сделан обзор литературы по такой проблеме, как боль в спине (дорсалгия). Представлены источники дорсалгии, актуальность проблемы, история вопроса, терминология, некоторые аспекты патогенеза, Международная классификация болезней 10-го пересмотра, три типа Модик-изменений тел позвонков при магнитно-резонансной томографии у пациентов с грыжей межпозвоночного диска, причины спонтанного регресса грыжи диска, диагностика заболеваний с болью в спине, критерии неспецифической (скелетно-мышечной) боли, критерии мышечно-тонического и миофасциального болевых синдромов, радикулопатии, сигналы опасности и основные принципы терапии. В работе авторы приводят современную классификацию заболеваний – источников болевого синдрома в спине и их дифференциально-диагностические критерии. The article reviews the literature on such an issue as back pain (dorsalgia). Sources of dorsalgia, relevance of the issue, background, terminology, several aspects of pathogenesis are presented. Back pain and the International Classification of Diseases 10th revision, three types of Modic changes in vertebral bodies on magnetic resonance imaging in patients with herniated disc, causes of spontaneous regression of herniated disc, diagnostic of conditions involving back pain, as well as criteria of nonspecific (musculoskeletal) pain, criteria of muscular and tonic and myofascial pain syndromes, radiculopathy, danger signals and basic principles of therapy are outlined. The authors give a modern classification of conditions being sources of back pain syndrome and their differential diagnostic criteria.

10.34883/pi.2024.14.3.050

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High-threshold primary afferent supply of spinal lamina X neurons

Pain (2019)

Volodymyr Krotov Anastasia Tokhtamysh Boris V. Safronov Pavel Belan Nana Voitenko

The spinal gray matter region around the central canal, lamina X, is critically involved in somatosensory processing and visceral nociception. Although several classes of primary afferent fibers terminate or decussate in this area, little is known about organization and functional significance of the afferent supply of lamina X neurons. Using the hemisected ex vivo spinal cord preparation, we show that virtually all lamina X neurons receive primary afferent inputs, which are predominantly mediated by the high-threshold Aδ- fibers and C-fibers. In two-thirds of the neurons tested, the inputs were monosynaptic, implying a direct targeting of the population of lamina X neurons by the primary nociceptors. Beside the excitatory inputs, 48% of the neurons also received polysynaptic inhibitory inputs. A complex pattern of interactions between the excitatory and inhibitory components determined the output properties of the neurons, one-third of which fired spikes in response to the nociceptive dorsal root stimulation. In this respect, the spinal gray matter region around the central canal is similar to the superficial dorsal horn, the major spinal nociceptive processing area. We conclude that lamina X neurons integrate direct and indirect inputs from several types of thin primary afferent fibers and play an important role in nociception.

Lamina

10.1097/j.pain.0000000000001586

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Phenotypes of Motor Deficit and Pain after Experimental Spinal Cord Injury

Bioengineering (2022)

Volodymyr Krotov Volodymyr Мedvediev Ibrahim Abdallah Arseniy Bozhenko Mykhailo Tatarchuk

Motor disability is a common outcome of spinal cord injury (SCI). The recovery of motor function after injury depends on the severity of neurotrauma; motor deficit can be reversible, at least partially, due to the innate tissue capability to recover, which, however, deteriorates with age. Pain is often a comorbidity of injury, although its prediction remains poor. It is largely unknown whether pain can attend motor dysfunction. Here, we implemented SCI for modelling severe and moderate neurotrauma and monitored SCI rats for up to 5 months post-injury to determine the profiles of both motor deficit and nociceptive sensitivity. Our data showed that motor dysfunction remained persistent after a moderate SCI in older animals (5-month-old); however, there were two populations among young SCI rats (1 month-old) whose motor deficit either declined or exacerbated even more over 4-5 weeks after identical injury. All young SCI rats displayed changed nociceptive sensitivity in thermal and mechanical modalities. The regression analysis of the changes revealed a population trend with respect to hyper- or hyposensitivity/motor deficit. Together, our data describe the phenotypes of motor deficit and pain, the two severe complications of neurotrauma. Our findings also suggest the predictability of motor dysfunction and pain syndromes following SCI that can be a hallmark for long-term rehabilitation and recovery after injury.

10.3390/bioengineering9060262

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Nerve Preparation and Recordings for Pharmacological Tests of Sensory and Nociceptive Fiber Conduction Ex Vivo

BIO-PROTOCOL (2024)

Volodymyr Krotov Olga Kopach

Measuring signal propagation through nerves is a classical electrophysiological technique established decades ago to evaluate sensory and motor functions in the nervous system. The whole-nerve preparation provides a valuable model to investigate nerve function ex vivo; however, it requires specific knowledge to ensure successful and stable measurements. Although the methodology for sciatic nerve recordings has long existed, a method for reliable and long-lasting recordings from myelinated and non-myelinated (nociceptive) fibers still needs to be adapted for pharmacological testing. This protocol takes benefits from epineurium sheath removal for pharmacological tests and provides a detailed description of how to make accurate nerve preparations, from the dissection and handling of nerves to epineurium cleaning, fabrication of adaptable suction electrodes for appropriate fiber stimulation and recordings, setting of electrophysiological protocols for compound action potential (CAP) recordings to distinguish between myelinated and non-myelinated (nociceptive) fibers, and finally to the analysis of the datasets of CAP components. We also demonstrate the feasibility of CAP recordings from individual branches in epineurium-free nerve preparations and provide clues to help retain nerve viability and maintain stable recordings over time. Although a sciatic nerve preparation was used here, the methodology can be applied to other nerve-type preparations. Key features • Detailed and simplified protocol for peripheral nerve preparation for recording sensory inputs ex vivo. • Recordings from myelinated and non-myelinated (nociceptive) fibers can be performed hours after nerve preparation. • The protocol involves the epineurium removal to facilitate drug permeability into nerve tissue for pharmacological tests. • The protocol allows physiological and pathological studies (pain/chronic pain conditions).

Epineurium

Sensory nerve

Nerve fiber

Ex vivo

10.21769/bioprotoc.4969

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