Journal of Critical Reviews

ISSN- 2394-5125 Vol 7, Issue 12, 2020

MOLECULAR MECHANISMS OF SYNAPTIC PRUNING REGULATION

1V.V. Kuznetsov, 2E.V. Kruchinin, 3K.M. Autlev, 3E.L. Yanin, 2F.S. Aliev

1Medical Faculty of Federal State Budgetary Educational Institution of Higher Education "Tyumen State Medical University" of the Ministry of Health of the Russian Federation, Tyumen, Russia 2Department of General Surgery of Federal State Budgetary Educational Institution of Higher Education "Tyumen State Medical University" of the Ministry of Health of the Russian Federation, Tyumen, Russia 3Department of Surgical Diseases of Federal State Budgetary Educational Institution of Higher Education "Tyumen State Medical University" of the Ministry of Health of the Russian Federation, Tyumen, Russia E-mail: [email protected]

Received: 10.03.2020 Revised: 11.04.2020 Accepted: 12.05.2020

Abstract Recently, more information has appeared in the scientific literature on the role of synaptic pruning in the development of many diseases of the nervous system. Synaptic pruning is the elimination of excess , thereby leading to optimization and increase the efficiency of the neural network. Excessive or insufficient synaptic pruning may underlie some disorders of the nervous system, including autism, , and epilepsy. There are also neurodegenerative diseases, which are based on the death of , presumably in connection with reactivation of pruning at a later age. However, the mechanisms of synaptic pruning are not well known so far. Prior to understanding the significance of pruning in pathological conditions, it is necessary to study more in detail and consider its physiological function. This literature review reveals the main mechanisms and features of the occurrence of this process.

Keywords: synaptic pruning, neurodegeneration, neurobiology.

© 2020 by Advance Scientific Research. This is an open-access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.31838/jcr.07.12.93

INTRODUCTION implementation of this process in ontogenesis are examined. Starting from the earliest stages of embryonic development and continuing through the first two years of life, new neurons and synapses form at an amazing speed, reaching 40,000 new FRAGMENTATION, RETRACTION synapses per second. As a result of this process, the number of The structures of the nervous system of mammals, in particular synapses formed far exceeds the functionally necessary values mice, and insects (drosophila) were most often used as models for the individual. At this stage, a mechanism called synaptic for studying various mechanisms of pruning. “Local pruning occurs. Its essence lies in the “trimming” of excess fragmentation” was revealed in the study of the 5th layer of synapses, thereby optimizing and increasing the efficiency of cortical neurons and cells of the retinal ganglion of mice, the the neural network. This process continues until the age of 10, mushroom body and dendritic arborization of drosophila. With when about 50% of synapses present at the age of 2 years are this mechanism, either the number of processes or their excess eliminated. The pattern by which the processes follow and the length with the formation of fragments decreases. The time spent on them depend on the area of the brain in which regulatory mechanism of this pathway was examined only on these mechanisms are implemented [1]. the model of dendritic arborization differentiation. In this case, there is a hypothesis that fragmentation is based on the local Recent studies point to the key role of glial cells in synaptic activity of caspases [4]. In this case, local sublethal activity of pruning in various parts of the nervous system. They also caspases at the level is important, which avoids cell revealed a number of critical signaling pathways between ; in most studies, all mechanisms are reduced to and neurons. At the same time, excessive or insufficient activation of the Cas system [5]. Fragments of the processes synaptic pruning may underlie some disorders of the subsequently undergo utilization with the participation of glial development of the nervous system, including autism, and other surrounding cells exhibiting the features of schizophrenia and epilepsy. The reverse situation is phagocytes. Fragments are absorbed and their lysosomal neurodegenerative diseases based on the death of neurons, destruction occurs [6]. Pruning by fragmentation is initiated by presumably in connection with reactivation of pruning at a later TGF-B receptors. Myoglianin as the ligand for these receptors is age. There are various hypotheses in the history of studying the produced by the surrounding glia, which again emphasizes its importance of pruning. Some researchers consider this role in pruning processes. There is also a family of phenomenon as an inevitable result of synaptic maturation, immunoglobulins that facilitate signaling of the TGF-B receptor devoid of any significance. Others suggested that synapses complex. Further, the signaling pathway leads to the initiation formed and amplified in the early stages of life could be of the pruning program through transcriptional induction of the destructive to the functioning of memory, namely, when new steroid Ecdisone. However, the role of the latter is not information is consolidated. Thus, the elimination of a part of clearly proven [7]. Retraction involves the reabsorption of neural connections will allow avoiding conflict, and improve and changes in the proximal parts of the latter without overall performance. During the analysis of the models of the formation of fragments. Retraction was specifically detected associative memory networks, it was concluded that the in thalamocortical neurons and Cajal-Retzius cells. In studies, it decrease in performance of the entire system due to pruning is was revealed that this mechanism was mainly used to get rid of very insignificant, in contrast to the resulting rationalization of small fragments of axons. The regulatory component of this energy expenditure [2]. mechanism is associated with signaling complexes consisting of -2 and -A. In the , the ligand of the The subtle mechanisms of regulatory processes that occur receptor complex is -3F, expressed around the during the “trimming” of synapses are not well understood. signal zone [8]. However, it is known that glial cells play a central role in these rearrangements [3]. An important aspect is that synaptic pruning can be the cause of the above age-related changes in the EFFECT OF MITOCHONDRIAL METABOLISM OF REACTIVE , as well as many pathological processes. OXYGEN SPECIES In this work, the role of pruning in pathological processes will In the hypothesis provided by James N. Cobley, a new vision on be considered, and the applied mechanisms for the the role of reactive oxygen species (ROS) in the body arose. In

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contrast to the classical idea of their damaging function, the idea were identified that play a role in synaptic rearrangements: of their possible participation in synaptic pruning processes neuronal pentraxins and the MHC class I proteins family and was considered. According to the hypothesis, the association of receptors). Components of the complement system can interact mitochondrial ROS with pruning can be justified by observing with the molecules mentioned above to eliminate synapses. their metabolism. The production of ROS increases in inactive According to studies, the deficiency of pentraxins and MHC-I synapses, and decreases in more active ones. At the same time, molecules also led to defects of eye-specific segregation in apoptosis is activated in inactive synapses. This correlation is dorsolateral geniculate nucleus cells [14]. substantiated by three main modes of ROS production by mitochondria depending on the energy expenditure of the cell [9]. Active synapse highly needs ATP. The release of a POSTNATAL DEVELOPMENT OF THE NERVOUS SYSTEM IS neurotransmitter, maintenance of ionic gradients, recirculation ASSOCIATED WITH THE GENERATION OF EXCESS of a vesicle pool require large resources. According to P. NEURONAL SYNAPSES, Murphy, under such conditions, mitochondria will produce followed by selective elimination and maturation of the much less ROS. Given the low consumption of ATP, the situation remaining synapses. This process is observed in all parts of the will be reversed and mitochondria begin to produce large nervous system, including the neuromuscular synapse. The key volumes of ROS. According to the hypothesis, mitochondrial O2- link in synaptic pruning, starting from the peripheral /H2O2 plays the role of both a signaling component and neuromuscular synapse to synapses in the cortex, activates the processes of pruning. For this, just the old vision hippocampus, thalamus, is neuroglia, demonstrated in of the destructive properties of ROS cannot be enough. The numerous studies [15, 16, 17, 18, 19, 20]. The primary stage of evidence of their controlled synthesis is required, which is synaptic pruning ensures the correct formation of sensory confirmed by the theses: ROS production can be predicted by circuits (for example, processing tactile, visual and auditory the methods described by Murphy and colleagues. There is no information) and executive circuits (including those regulating correlation with the delivery of exogenous O2 into the cell (low memory and behavior) of the brain. The latter refers to the production of O2-, despite the high supply of O2). If necessary, neonatal period [21]. elimination processes can be launched. There are also feedback In , synaptic pruning is most active in such parts of mechanisms. Mitochondrial O2-/H2O2 disables prolyl the brain as the prefrontal cortex, which require remodeling to hydroxylase, thereby activating HIF1-α, hypoxia-inducible achieve mature internal behavior, target planning and impulse factor 1-alpha, that initiates adaptive mechanisms. HIF1-α control [22]. Numerous neuromuscular synapses (NMSs) are transcribes NADH dehydrogenase subcomplexes that block O2- trimmed with the transition from polysynaptic innervation to production [10]. The mechanism by which ROS affect pruning is monosynaptic one. Synaptic trimming of the NMSs is the local caspase activity (sublethal apoptosis). There are two simplest and most accessible structure for study. During the critical mechanistic connections. First, Kagan et al. provide embryonic development of mice, motor end plates are convincing evidence that, during the initiation of apoptosis, innervated by approximately ten axons from different motor cytochrome C (Cyt C) binds to cardiolipin (CL) which is the main neurons. In the first and second postnatal weeks, multi-inner phospholipid of the inner mitochondrial membrane, before terminal plates lose synaptic inputs, becoming single ones [23]. using H2O2 to oxidize it. Oxidized CL and Cyt c translocate to Several mechanisms that are involved in this process are the outer membrane, where they promote the release of the revealed: Acetylcholine is the main mediator of NMSs and an pro-apoptotic factor associated with the permeability of the indicator of motor activity. Terminal Schwann cells outer mitochondrial membrane [11]. This discovery allows us (tSCs) show intracellular Ca2 + jumps in response to to recognize the mitochondrial synthesis of O2-/H2O2 as a Acetylcholine isolated from the presynaptic membrane. necessary early pro-apoptotic stage that allows Cyt C to Presumably, these peaks decode the synaptic efficiency of each appropriate peroxidase activity. Secondly, Green's group ; the effect of neuromuscular NMDA receptors in the NMSs showed that NDUFS1, a factor regulating the production of O2- [24, 25]. In a study using NMDA receptor antagonists, /H2O2, acts as a mechanism for the deliberate synthesis of ROS knockdown receptors, inhibition of glutamate synthesis, as well for apoptosis and, as a result, trimming of synapses [10]. as the addition of agonists, it was shown that this mediator system affects synaptic pruning and its blocking drastically COMPLEMENT SYSTEM slows down this process and, in contrast, its activation Recent discoveries revealed the unexpected role of the significantly accelerated pruning. Major histocompatibility complement system in the elimination of synapses. The studies complex (MHC) is expressed in the developing NMS and its were conducted on a model of retinal ganglion cells (RGCs) deficiency delays the transition to mono-innervation. dorsolateral geniculate nucleus cells of the mouse thalamus. Neuregulin-1 type 3 (NRG1-III), being a member of the proteins The most important components of the classical activation family that regulate the development of the nervous system, pathway are C1q, C3, and C4, whose deficiency led to defects in prevents apoptosis of terminal Schwann cells (tSCs) during the pruning processes in mice [12]. Moreover, the C3 component early postnatal period and promotes their mitosis with localized in the axonal terminals of RGCs, dorsolateral increased phagocytic activity in relation to motor axon geniculate nucleus cells, is identified by the immunoreactivity terminals [26, 27, 28]. Most isoforms of the neuregulin-1 of the vesicular glutamate transporter-2, which suggests the protein are produced in the form of proprotein by neurons, and role of the C3 protein in the labeling of synapses for subsequent then undergo proteolytic maturation [29, 30, 31]. The elimination. It is worth mentioning that complement proteolytic enzyme BACE-1 catalyzes the formation of active components are synthesized locally, not being able to pass the Neuroregulin-1 type 3 (NRG1-III) and its absence slows down blood-brain barrier. For the most part, C1q expression is synaptic pruning in the NMS. All the mechanisms above are an carried out by , but can also occur in some neuronal integral part of one process, the final result of which is the regions, which is characteristic of RGC. Induction of expression activation of the caspase-3 enzyme with subsequent in the latter occurs due to transforming beta of the remains of synaptic terminals by Schwann (TRF-β). The increase in C1q synthesis occurs with age. The C3 cells and the transition to mono-innervation. In various parts of component, in contrast to C1q, is less expressed. The role of the central nervous system, the main cell in pruning is neuroglia microglia in synthesis is important only in the context of [32, 33, 34, 35]. In contrast to the peripheral system in the pathological processes. In the process of development, the central nervous system, one of the key elements in synaptic source is not identified. Like C1q, in the context of the visual pruning is the complement system. The latter is considered as a system, C4 protein is expressed by RGC during the synaptic system of rapid and local immunological surveillance, however, clearing dorsolateral geniculate nucleus cells. Ultimately, recent studies [36, 37] reveal many new complement functions pruning is carried out due to the same microglia, however, the in the brain that go far beyond the protective and inflammatory process is complement dependent [13]. In addition to processes. Complement activation and its effector functions are complement, several other immune system-related molecules strictly regulated by a large group of various molecules that are widely expressed in the body, including the so-called

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