Synaptic Effects Research Articles

Department of Pharmacology of the Imperial Medical and Surgical (Military Medical) Academy: History of the second century of existence (1899–2000)

The study presents the history of the development of the Department of Pharmacology of Medical and Surgical (since 1881 Military Medical) Academy with an emphasis on the second century of its existence (18992000). This period was marked by the improvement of both the teaching of the discipline, based on new pharmacological data, and the introduction of new methods of drug research. A significant event was the release of a two-volume edition of N.P. Kravkovs Fundamentals of Pharmacology in 19041905, which was based on the introduction of the latest achievements of scientific knowledge in the field of pharmacology. The textbook N.P. Kravkov withstood 14 editions (the last one was published in 1936, 12 years after the authors death) and served as a model for the creation of all subsequent domestic textbooks and manuals on pharmacology in the 20th century. In experimental pharmacology, the method of isolated organs (N.P. Kravkov et al.) has been widely used as a universal method for quantifying pharmacological effects. In the 1920s, ideas about the synaptic effect of drugs were actively introduced (S.V. Anichkov et al.), and the effects of N-cholinergic drugs realized through the sinocarotid zone of the carotid artery were discovered and studied. Biochemical studies began to be widely used, which started with the works of N.P. Kravkov and continued by N.V. Lazarev, V.M. Vinogradov, and A.V. Smirnov. Clinical pharmacology was created and promoted after the discovery and first use of the intravenous anesthetic hedonal (N.P. Kravkov), particularly developed in the studies by N.V. Lazarev and V.M. Vinogradov. New ideas about antihypoxants and actoprotectors were formulated (V.M. Vinogradov) to increase combat capability and was successfully used in military pharmacology at the end of the 20th century (V.M. Vinogradov and A.V. Smirnov). Therefore, with these achievements, the department has succeeded in both the academic and scientific fields.

Decreased nitrosylation of CaMKII causes aging-associated impairments in memory and synaptic plasticity in mice.

CaMKII has molecular memory functions because transient calcium ion stimuli can induce long-lasting increases in its synaptic localization and calcium ion-independent (autonomous) activity, thereby leaving memory traces of calcium ion stimuli beyond their duration. The synaptic effects of two mechanisms that induce CaMKII autonomy are well studied: autophosphorylation at threonine-286 and binding to GluN2B. Here, we examined the neuronal functions of additional autonomy mechanisms: nitrosylation and oxidation of the CaMKII regulatory domain. We generated a knock-in mouse line with mutations that render the CaMKII regulatory domain nitrosylation/oxidation-incompetent, CaMKIIΔSNO, and found that it had deficits in memory and synaptic plasticity that were similar to those in aged wild-type mice. In addition, similar to aged wild-type mice, in which CaMKII was hyponitrosylated, but unlike mice with impairments of other CaMKII autonomy mechanisms, CaMKIIΔSNO mice showed reduced long-term potentiation (LTP) when induced by theta-burst stimulation but not high-frequency stimulation (HFS). As in aged wild-type mice, the HFS-LTP in the young adult CaMKIIΔSNO mice required L-type voltage-gated calcium ion channels. The effects in aged mice were likely caused by the loss of nitrosylation because no decline in CaMKII oxidation was detected. In hippocampal neurons, nitrosylation of CaMKII induced its accumulation at synapses under basal conditions in a manner mediated by GluN2B binding, like after LTP stimuli. However, LTP-induced synaptic CaMKII accumulation did not require nitrosylation. Thus, an aging-associated decrease in CaMKII nitrosylation may cause impairments by chronic synaptic effects, such as the decrease in basal synaptic CaMKII.

Neurophysiological mechanisms of deep brain stimulation across spatiotemporal resolutions.

Deep brain stimulation is a neuromodulatory treatment for managing the symptoms of Parkinson's disease and other neurological and psychiatric disorders. Electrodes are chronically implanted in disease-relevant brain regions and pulsatile electrical stimulation delivery is intended to restore neurocircuit function. However, the widespread interest in the application and expansion of this clinical therapy has preceded an overarching understanding of the neurocircuit alterations invoked by deep brain stimulation. Over the years, various forms of neurophysiological evidence have emerged which demonstrate changes to brain activity across spatiotemporal resolutions; from single-neuron, to local field potential, to brain-wide cortical network effects. Though fruitful, such studies have often led to debate about a singular putative mechanism. In this Update we aim to produce an integrative account of complementary instead of mutually exclusive neurophysiological effects to derive a generalizable concept of the mechanisms of deep brain stimulation. In particular, we offer a critical review of the most common historical competing theories, an updated discussion on recent literature from animal and human neurophysiological studies, and a synthesis of synaptic and network effects of DBS across scales of observation, including micro-, meso-, and macroscale circuit alterations.

MSK1 is required for the beneficial synaptic and cognitive effects of enriched experience across the lifespan.

Positive experiences, such as social interaction, cognitive training and physical exercise, have been shown to ameliorate some of the harms to cognition associated with ageing. Animal models of positive interventions, commonly known as environmental enrichment, strongly influence neuronal morphology and synaptic function and enhance cognitive performance. While the profound structural and functional benefits of enrichment have been appreciated for decades, little is known as to how the environment influences neurons to respond and adapt to these positive sensory experiences. We show that adult and aged male wild-type mice that underwent a 10-week environmental enrichment protocol demonstrated improved performance in a variety of behavioural tasks, including those testing spatial working and spatial reference memory, and an enhancement in hippocampal LTP. Aged animals in particular benefitted from enrichment, performing spatial memory tasks at levels similar to healthy adult mice. Many of these benefits, including in gene expression, were absent in mice with a mutation in an enzyme, MSK1, which is activated by BDNF, a growth factor implicated in rodent and human cognition. We conclude that enrichment is beneficial across the lifespan and that MSK1 is required for the full extent of these experience-induced improvements of cognitive abilities, synaptic plasticity and gene expression.

Bio‐Inspired Artificial Fast‐Adaptive and Slow‐Adaptive Mechanoreceptors With Synapse‐Like Functions

AbstractDevelopment of artificial mechanoreceptors capable of sensing and pre‐processing external mechanical stimuli is a crucial step toward constructing neuromorphic perception systems that can learn and store information. Here, bio‐inspired artificial fast‐adaptive (FA) and slow‐adaptive (SA) mechanoreceptors with synapse‐like functions are demonstrated for tactile perception. These mechanoreceptors integrate self‐powered piezoelectric pressure sensors with synaptic electrolyte‐gated field‐effect transistors (EGFETs) featuring a reduced graphene oxide channel. The FA pressure sensor is based on a piezoelectric poly(vinylidene fluoride‐trifluoroethylene) (P(VDF‐TrFE)) thin film, while the SA pressure sensor is enabled by a piezoelectric ionogel with the piezoelectric‐ionic coupling effect based on P(VDF‐TrFE) and an ionic liquid. Changes in post‐synaptic current are achieved through the synaptic effect of the EGFET by regulating the amplitude, number, duration, and frequency of tactile stimuli (pre‐synaptic pulses). These devices have great potential to serve as artificial biological mechanoreceptors for future artificial neuromorphic perception systems.

Alcohol dependence interactions with sex-specific stress-related neuropeptide and alcohol CeA synaptic effects

Alcohol dependence interactions with sex-specific stress-related neuropeptide and alcohol CeA synaptic effects

Synaptic effect and non-volatile switching modulated by LiCoO2/boehmite composite layer

In this study, a memristor was modulated to exhibit both synaptic effects and non-volatile switching through the use of a composite layer made of LiCoO2 and boehmite. At low applied bias, the memristor displayed clear synaptic behavior, functioning as an artificial neuron. At high applied bias, the memristor functioned as a binary system memory with non-volatile switching capabilities. The observed properties are thought to result from the coexistence of dual-ion mechanisms in the LiCoO2/boehmite composite layer, with the migration of Li ions and H ions controlling the synaptic effect and non-volatile switching, respectively. This study presents a promising material system for the development of novel multi-functional devices and intelligent electronics.

Comparative assessment of the effects of DREADDs and endogenously expressed GPCRs in hippocampal astrocytes on synaptic activity and memory.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have proven themselves as one of the key in vivo techniques of modern neuroscience, allowing for unprecedented access to cellular manipulations in living animals. With respect to astrocyte research, DREADDs have become a popular method to examine the functional aspects of astrocyte activity, particularly G-protein coupled receptor (GPCR)-mediated intracellular calcium (Ca2+) and cyclic adenosine monophosphate (cAMP) dynamics. With this method it has become possible to directly link the physiological aspects of astrocytic function to cognitive processes such as memory. As a result, a multitude of studies have explored the impact of DREADD activation in astrocytes on synaptic activity and memory. However, the emergence of varying results prompts us to reconsider the degree to which DREADDs expressed in astrocytes accurately mimic endogenous GPCR activity. Here we compare the major downstream signaling mechanisms, synaptic, and behavioral effects of stimulating Gq-, Gs-, and Gi-DREADDs in hippocampal astrocytes of adult mice to those of endogenously expressed GPCRs.

An Image Detection–Memory–Recognition Artificial Visual Unit Based on Dual‐Gate Phototransistors

Optoelectronic synapses integrating sensing–memory–processing functions have great advantages in neuromorphic computing for visual information processing and complex learning, recognition, and memory in an energy‐efficient manner. Herein, a light‐induced bidirectional response is demonstrated in the proposed WSe2/MoS2 junction field‐effect transistor (JFET) with an extra Ge back gate. The WSe2/MoS2 JFET exhibits high responsivity and detectivity owing to effective modulation by the top junction and back dielectric gates. The unique bidirectional photoresponse and interfacial state storage properties of the device result in significant synaptic excitatory effects under visible light stimulation and remarkable synaptic inhibitory effects under infrared illumination. Optical storage with visible light and optical erasure with infrared light can be achieved in the device based on its synaptic behavior. The conductance changes under different types of illumination can be used to mimic the weight update in a neural network for image recognition. A high accuracy exceeding 98% was achieved in handwritten digit recognition. This visible and infrared dual‐band phototransistor, which integrates image perception, memory, and recognition functionalities, provides a promising solution for self‐driving, surveillance, computer vision, and biomedical imaging applications.

Chronic ethanol induces a pro-inflammatory switch in interleukin-1β regulation of GABAergic signaling in the medial prefrontal cortex of male mice

Neuroimmune pathways regulate brain function to influence complex behavior and play a role in several neuropsychiatric diseases, including alcohol use disorder (AUD). In particular, the interleukin-1 (IL-1) system has emerged as a key regulator of the brain’s response to ethanol (alcohol). Here we investigated the mechanisms underlying ethanol-induced neuroadaptation of IL-1β signaling at GABAergic synapses in the prelimbic region of the medial prefrontal cortex (mPFC), an area responsible for integrating contextual information to mediate conflicting motivational drives. We exposed C57BL/6J male mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and conducted ex vivo electrophysiology and molecular analyses. We found that the IL-1 system regulates basal mPFC function through its actions at inhibitory synapses on prelimbic layer 2/3 pyramidal neurons. IL-1β can selectively recruit either neuroprotective (PI3K/Akt) or pro-inflammatory (MyD88/p38 MAPK) mechanisms to produce opposing synaptic effects. In ethanol naïve conditions, there was a strong PI3K/Akt bias leading to a disinhibition of pyramidal neurons. Ethanol dependence produced opposite IL-1 effects - enhanced local inhibition via a switch in IL-1β signaling to the canonical pro-inflammatory MyD88 pathway. Ethanol dependence also increased cellular IL-1β in the mPFC, while decreasing expression of downstream effectors (Akt, p38 MAPK). Thus, IL-1β may represent a key neural substrate in ethanol-induced cortical dysfunction. As the IL-1 receptor antagonist (kineret) is already FDA-approved for other diseases, this work underscores the high therapeutic potential of IL-1 signaling/neuroimmune-based treatments for AUD.

Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity

Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARγ2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI's pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI's synaptic effects and dampening hyperexcitability.

A biogenesis construction of CuO@MWCNT via Chenopodium album extract: an effective electrocatalyst for synaptic plasticity neurodegenerative drug pollutant detection.

Clioquinol (CLQ) is one of the most toxic halogenated neurodegenerative drugs, and its synaptic plasticity effect directly affects human health and the environment. Cupric oxide (CuO) is an ideal electrocatalyst owing to its earth-abundance, non-toxic nature, and cost-effectiveness. Since phenolate oxygen and pyridine nitrogen in CLQ act as an electron donor and pave the way for detection with Cu2+ ions in the CuO. Designing the architecture of CuO with a multi-walled carbon nanotube (MWCNT) is a sensible strategy to improve the electrochemical activity of the developed sensor. Inspired by the bio-synthesis and green processing, we have demonstrated the in-situ synthesis of CuO nanosphere-decorated MWCNT by Chenopodium album leaf extract through a sonochemical approach and explored its electrochemical sensing performance toward CLQ. The physical comprehensive characterization of prepared nanocomposite was investigated by various microscopic and spectroscopic techniques. For comparison studies, the CuO nanosphere was prepared by the same preparation process without MWCNT. Based on the physical characterization outcomes, the morphological nature of CuO was observed to be a sphere-like structure, which was decorated on the MWCNT with an average crystallite size of 16nm (± 1nm). Based on the electrochemical studies, the fabricated nanocomposite exhibits a wider linear range of 0.025-1375μM, with a minimum detection limit of 4.59nML-1 toward CLQ. The viability examination on the biological matrix obtained considerable spike recoveries.

Different synaptic mechanisms of intermittent and continuous theta-burst stimulations in a severe foot-shock induced and treatment-resistant depression in a rat model

Treatment-resistant depression (TRD) is a condition wherein patients with depression fail to respond to antidepressant trials. A new form of repetitive transcranial magnetic stimulation (rTMS), called theta-burst stimulation (TBS), which includes intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS), is non-inferior to rTMS in TRD treatment. However, the mechanism of iTBS and cTBS underlying the treatment of TRD in the prefrontal cortex (PFC) remains unclear. Hence, we applied foot-shock stress as a traumatic event to develop a TRD rat model and investigated the different mechanisms of iTBS and cTBS. The iTBS and cTBS treatment were effective in depressive-like behavior and active coping behavior. The iTBS treatments improved impaired long-term potentiation and long-term depression (LTD), whereas the cTBS treatment only improved aberrant LTD. Moreover, the decrease in mature brain-derived neurotrophic factor (BDNF)-related protein levels were reversed by iTBS treatment. The decrease in proBDNF-related protein expression was improved by iTBS and cTBS treatment. Both iTBS and cTBS improved the decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and downregulation of mammalian target of the rapamycin (mTOR) signaling pathway. The iTBS produces both excitatory and inhibitory synaptic effects, and the cTBS only produces inhibitory synaptic effects in the PFC.

Depletion of microglial BDNF increases susceptibility to the behavioral and synaptic effects of chronic unpredictable stress

In the medial prefrontal cortex (PFC), chronic stress reduces synaptic expression of glutamate receptors, leading to decreased excitatory signaling from layer V pyramidal neurons and working memory deficits. One key element driving these changes is a reduction in brain-derived neurotrophic factor (BDNF) signaling. BDNF is a potent mediator of synaptic growth and deficient BDNF signaling has been linked to stress susceptibility. Prior studies indicated that neurons are the primary source of BDNF, but more recent work suggests that microglia are also an important source of BDNF. Adding to this, our work showed that 14 days of chronic unpredictable stress (CUS) reduced Bdnf transcript in PFC microglia, evincing its relevance in the effects of stress. To explore this further, we utilized transgenic mice with microglia-specific depletion of BDNF (Cx3cr1Cre/+:Bdnffl/fl) and genotype controls (Cx3cr1Cre/+:Bdnf+/+). In the following experiments, mice were exposed to a shortened CUS paradigm (7 days) to determine if microglial Bdnf depletion promotes stress susceptibility. Analyses of PFC microglia revealed that Cx3cr1Cre/+:Bdnffl/fl mice had shifts in phenotypic markers and gene expression. In a separate cohort, synaptoneurosomes were collected from the PFC and western blotting was performed for synaptic markers. These experiments showed that Cx3cr1Cre/+:Bdnffl/fl mice had baseline deficits in GluN2B, and that 7 days of CUS additionally reduced GluN2A levels in Cx3cr1Cre/+:Bdnffl/fl mice, but not genotype controls. Behavioral and cognitive testing showed that this coincided with exacerbated stress effects on temporal object recognition in Cx3cr1Cre/+:Bdnffl/fl mice. These results indicate that microglial BDNF promotes glutamate receptor expression in the PFC. As such, mice with deficient microglial BDNF had increased susceptibility to the behavioral and cognitive consequences of stress.

Selective stimulation of nociceptive small fibers during intraepidermal electrical stimulation: Experiment and computational analysis.

Electrical stimulation of skin nociceptors is gaining attention in pain research and peripheral neuropathy diagnosis. However, the optimal parameters for selective stimulation are still difficult to determine because they require simultaneous characterization of the electrical response of small fibers (Aδ- and C-fibers). In this study, we measured the in vivo electrical threshold responses of small fibers to train-pulse stimulation in humans for the first time. We also examined selective stimulation via a computational model, which combines electrical analysis, and terminal fiber and synaptic models, including the first cutaneous pain C-fiber model. Selective stimulation of small fibers is performed by injecting train-pulse stimulation via coaxial electrodes with an intraepidermal needle tip at varying pulse counts and frequencies. The activation Aδ- or C-fibers was discriminated from the differences in reaction time. Aδ-fiber elicited a pinpricking sensation with a mean reaction time of 0.522 s, and C-fiber elicited a tingling sensation or slight burning itch with a mean reaction time of 1.243 s. The implemented multiscale electrical model investigates synaptic effects while considering stimulation waveform characteristics. Experimental results showed that perception thresholds decreased with the number of consecutive pulses and frequency up to convergence (five pulses or 70 Hz) during the selective stimulation of Aδ- and C-fibers. Considering the synaptic properties, the optimal stimulus conditions for selective stimulation of Aδ- vs. C-fibers were train of at least four pulses and a frequency of 40-70 Hz at a pulse width of 1 ms. The experimental results were modeled with high fidelity by incorporating temporal synaptic effects into the computational model. Numerical analysis revealed terminal axon thickness to be the most important biophysical factor affecting threshold variability. The computational model can be used to estimate perception thresholds while understanding the mechanisms underlying the selective stimulation of small fibers. The parameters derived here are important in exploring selective stimulation between Aδ- and C-fibers for diagnosing neuropathies.

Synaptic Effects Induced by Alcohol.

Ethanol (EtOH) has effects on numerous cellular molecular targets, and alterations in synaptic function are prominent among these effects. Acute exposure to EtOH activates or inhibits the function of proteins involved in synaptic transmission, while chronic exposure often produces opposing and/or compensatory/homeostatic effects on the expression, localization, and function of these proteins. Interactions between different neurotransmitters (e.g., neuropeptide effects on release of small molecule transmitters) can also influence both acute and chronic EtOH actions. Studies in intact animals indicate that the proteins affected by EtOH also play roles in the neural actions of the drug, including acute intoxication, tolerance, dependence, and the seeking and drinking of EtOH. The present chapter is an update of our previous Lovinger and Roberto (Curr Top Behav Neurosci 13:31-86, 2013) chapter and reviews the literature describing these acute and chronic synaptic effects of EtOH with a focus on adult animals and their relevance for synaptic transmission, plasticity, and behavior.

Electrophysiology of Endocannabinoid Signaling.

Electrophysiological technique is an efficient tool for investigating the synaptic regulatory effects mediated by the endocannabinoid system. Stimulation of presynaptic type 1 cannabinoid receptor (CB1) is the principal mode by which endocannabinoids suppress transmitter release in the central nervous system, but a non-retrograde manner of functioning and other receptors have also been described. Endocannabinoids are key modulators of both short- and long-term plasticity. Here, we discuss ex vivo electrophysiological approaches to examine synaptic signaling induced by cannabinoid and endocannabinoid molecules in the mammalian brain.

Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders.

Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and in patients’ studies. In the last few years, palmitoylethanolamide (PEA), an endogenous lipid mediator, and its new composite, which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultra-micronization process (co-ultraPEALut), has been identified as a potential therapeutic agent in different disorders by exerting potential beneficial effects on neurodegeneration and neuroinflammation by modulating synaptic transmission. In this review, we will show the potential therapeutic effects of PEA in animal models and in patients affected by neurodegenerative disorders.

Hyperoside improves learning and memory deficits by amyloid β1-42 in mice through regulating synaptic calcium-permeable AMPA receptors

Alzheimer's disease (AD) is the most common degenerative disease and is indicative of dementia. The cerebral accumulation of amyloid β (Aβ), a crucial factor in AD, initiates synaptic and cognitive dysfunction. Therefore, the elevation of synaptic and cognitive functions may help manage dementia in AD. In this study, we suggest hyperoside as a synaptic function- and memory-enhancing agent. Hyperoside enhanced learning and memory in passive avoidance and object recognition tasks. Hyperoside facilitated synaptic long-term potentiation (LTP) in acute hippocampal slices. IEM-1460, a calcium-permeable amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) antagonist, blocked the facilitation effect of hyperoside. Hyperoside also induced N-methyl-d-aspartate receptor (NMDAR)-independent LTP, which was blocked by IEM-1460, suggesting the involvement of CP-AMPARs in the synaptic effects of hyperoside-mediated LTP. PKI (a PKA inhibitor) or SQ22536 (adenylyl cyclase, an AC inhibitor) blocked hyperoside-facilitated LTP and hyperoside-induced NMDAR-independent LTP. Hyperoside-enhanced learning and memory were blocked by IEM-1460, suggesting the involvement of CP-AMPARs in the effect of hyperoside on learning and memory. Finally, hyperoside ameliorated Aβ-induced memory impairments in an AD mouse model. These results suggest that hyperoside enhances learning and memory, and this may be due to the effect of CP-AMPARs.

Rabphilin-3A as a novel target to reverse α-synuclein-induced synaptic loss in Parkinson’s disease

Toxic aggregates of α-synuclein (αsyn) are considered key drivers of Parkinson’s disease (PD) pathology. In early PD, αsyn induces synaptic dysfunction also modulating the glutamatergic neurotransmission. However, a more detailed understanding of the molecular mechanisms underlying αsyn-triggered synaptic failure is required to design novel therapeutic interventions. Here, we described the role of Rabphilin-3A (Rph3A) as novel target to counteract αsyn-induced synaptic loss in PD. Rph3A is a synaptic protein interacting with αsyn and involved in stabilizing dendritic spines and in promoting the synaptic retention of NMDA-type glutamate receptors. We found that in vivo intrastriatal injection of αsyn-preformed fibrils in mice induces the early loss of striatal synapses associated with decreased synaptic levels of Rph3A and impaired Rph3A/NMDA receptors interaction. Modulating Rph3A striatal expression or interfering with the Rph3A/αsyn complex with a small molecule prevented dendritic spine loss and rescued associated early motor defects in αsyn-injected mice. Notably, the same experimental approaches prevented αsyn-induced synaptic loss in vitro in primary hippocampal neurons. Overall, these findings indicate that approaches aimed at restoring Rph3A synaptic functions can slow down the early synaptic detrimental effects of αsyn aggregates in PD.