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Journal of Cell Science Nov 2023Changes in cholesterol content of neuronal membranes occur during development and brain aging. Little is known about whether synaptic activity regulates cholesterol...
Changes in cholesterol content of neuronal membranes occur during development and brain aging. Little is known about whether synaptic activity regulates cholesterol levels in neuronal membranes and whether these changes affect neuronal development and function. We generated transgenic flies that express the cholesterol-binding D4H domain of perfringolysin O toxin and found increased levels of cholesterol in presynaptic terminals of Drosophila larval neuromuscular junctions following increased synaptic activity. Reduced cholesterol impaired synaptic growth and largely prevented activity-dependent synaptic growth. Presynaptic knockdown of adenylyl cyclase phenocopied the impaired synaptic growth caused by reducing cholesterol. Furthermore, the effects of knocking down adenylyl cyclase and reducing cholesterol were not additive, suggesting that they function in the same pathway. Increasing cAMP levels using a dunce mutant with reduced phosphodiesterase activity failed to rescue this impaired synaptic growth, suggesting that cholesterol functions downstream of cAMP. We used a protein kinase A (PKA) sensor to show that reducing cholesterol levels reduced presynaptic PKA activity. Collectively, our results demonstrate that enhanced synaptic activity increased cholesterol levels in presynaptic terminals and that these changes likely activate the cAMP-PKA pathway during activity-dependent growth.
Topics: Animals; Adenylyl Cyclases; Drosophila; Neuromuscular Junction; Presynaptic Terminals; Animals, Genetically Modified; Synaptic Transmission
PubMed: 37902091
DOI: 10.1242/jcs.261563 -
Progress in Neurobiology Jul 2021To form and maintain extremely intricate and functional neural circuitry, mammalian neurons are typically endowed with highly arborized dendrites and a long axon. The... (Review)
Review
To form and maintain extremely intricate and functional neural circuitry, mammalian neurons are typically endowed with highly arborized dendrites and a long axon. The synapses that link neurons to neurons or to other cells are numerous and often too remote for the cell body to make and deliver new proteins to the right place in time. Moreover, synapses undergo continuous activity-dependent changes in their number and strength, establishing the basis of neural plasticity. The innate dilemma is then how a highly complex neuron provides new proteins for its cytoplasmic periphery and individual synapses to support synaptic plasticity. Here, we review a growing body of evidence that local protein synthesis in discrete sites of the axon and presynaptic terminals plays crucial roles in synaptic plasticity, and that deregulation of this local translation system is implicated in various pathologies of the nervous system.
Topics: Animals; Axons; Neuronal Plasticity; Neurons; Presynaptic Terminals; Synapses
PubMed: 33845165
DOI: 10.1016/j.pneurobio.2021.102051 -
CNS & Neurological Disorders Drug... 2022Regulation of glutamate release is crucial for maintaining normal brain function, but excess glutamate release is implicated in many neuropathological conditions.... (Review)
Review
BACKGROUND
Regulation of glutamate release is crucial for maintaining normal brain function, but excess glutamate release is implicated in many neuropathological conditions. Therefore, the minimum glutamate release from presynaptic nerve terminals is an important neuroprotective mechanism.
OBJECTIVE
In this mini-review, we analyze the three B vitamins, namely vitamin B2 (riboflavin), vitamin B6 (pyridoxine), and vitamin B12 (cyanocobalamin), that affect the 4-aminopyridine (4- AP)-evoked glutamate release from presynaptic nerve terminal in rat and discuss their neuroprotective role.
METHODS
In this study, the measurements include glutamate release, DiSC3(5), and Fura-2.
RESULTS
The riboflavin, pyridoxine, and cyanocobalamin produced significant inhibitory effects on 4-aminopyridine-evoked glutamate release from rat cerebrocortical nerve terminals (synaptosomes) in a dose-dependent relationship. These presynaptic inhibitory actions of glutamate release are attributed to inhibition of physiologic Ca2+-dependent vesicular exocytosis but not Ca2+-independent nonvesicular release. These effects also did not affect membrane excitability, while diminished cytosolic (Ca2+)c through a reduction of direct Ca2+ influx Cav2.2 (N-type) and Cav2.1 (P/Q-type) Ca2+ channels, rather than through indirect Ca2+induced Ca2+ release from ryanodine-sensitive intracellular stores. Furthermore, their effects were attenuated by GF109203X and Ro318220, two protein kinase C (PKC) inhibitors, suggesting suppression of PKC activity. Taken together, these results suggest that riboflavin, pyridoxine, and cyanocobalamin inhibit presynaptic vesicular glutamate release from rat cerebrocortical synaptosomes, through the depression Ca2+ influx via voltage- dependent Cav2.2 (N-type) and Cav2.1 (P/Q-type) Ca2+ channels, and PKC signaling cascade.
CONCLUSION
Therefore, these B vitamins may reduce the strength of glutamatergic synaptic transmission and is of considerable importance as potential targets for therapeutic agents in glutamate- induced excitation-related diseases.
Topics: 4-Aminopyridine; Animals; Calcium; Calcium Channels, N-Type; Cerebral Cortex; Glutamic Acid; Male; Membrane Potentials; Presynaptic Terminals; Protein Kinase C; Rats; Rats, Sprague-Dawley; Signal Transduction; Synaptic Transmission; Synaptosomes; Vitamin B Complex
PubMed: 34477538
DOI: 10.2174/1871527320666210902165739 -
The FEBS Journal Feb 2022Voltage-gated calcium (Ca ) channels and their regulation by proteins at the synaptic cleft play a critical role in neurotransmission. These interactions fine-tune the... (Review)
Review
Voltage-gated calcium (Ca ) channels and their regulation by proteins at the synaptic cleft play a critical role in neurotransmission. These interactions fine-tune the synaptic response through the regulation of Ca entry into the presynaptic terminal and trigger the fusion of vesicles filled with neurotransmitters and peptides. Regulation of Ca channel intrinsic properties and their numbers at the active zones shape the timing and strength of synaptic function. Here, we provide an overview of a number of proteins reported to be part of Ca channel nanodomains at the synaptic cleft and the repercussions of these interactions for Ca channel trafficking, tethering at the active zone, and regulation of their biophysical properties. We summarize the current state of knowledge by which Ca channels are regulated at presynaptic sites.
Topics: Calcium; Calcium Channels; Calcium Signaling; Calcium-Binding Proteins; Humans; Neurons; Presynaptic Terminals; Synapses; Synaptic Transmission
PubMed: 33576127
DOI: 10.1111/febs.15759 -
Cell Reports Oct 2023Calcium (Ca) signaling is tightly regulated within a presynaptic bouton. Here, we visualize Ca signals within hippocampal presynaptic boutons using GCaMP8s tagged to...
Calcium (Ca) signaling is tightly regulated within a presynaptic bouton. Here, we visualize Ca signals within hippocampal presynaptic boutons using GCaMP8s tagged to synaptobrevin, a synaptic vesicle protein. We identify evoked presynaptic Ca transients (ePreCTs) that derive from synchronized voltage-gated Ca channel openings, spontaneous presynaptic Ca transients (sPreCTs) that originate from ryanodine sensitive Ca stores, and a baseline Ca signal that arises from stochastic voltage-gated Ca channel openings. We find that baseline Ca, but not sPreCTs, contributes to spontaneous glutamate release. We employ photobleaching as a use-dependent tool to probe nano-organization of Ca signals and observe that all three occur in non-overlapping domains within the synapse at near-resting conditions. However, increased depolarization induces intermixing of these Ca domains via both local and non-local synaptic vesicle turnover. Our findings reveal nanosegregation of Ca signals within a presynaptic terminal that derive from multiple sources and in turn drive specific modes of neurotransmission.
Topics: Synaptic Transmission; Synapses; Presynaptic Terminals; Synaptic Vesicles; Hippocampus; Calcium
PubMed: 37777959
DOI: 10.1016/j.celrep.2023.113201 -
Cells Oct 2022The concept of the tripartite synapse describes the close interaction of pre- and postsynaptic elements and the surrounding astrocyte processes. For glutamatergic...
The concept of the tripartite synapse describes the close interaction of pre- and postsynaptic elements and the surrounding astrocyte processes. For glutamatergic synapses, it is established that the presence of astrocytic processes and their structural arrangements varies considerably between and within brain regions and between synapses of the same neuron. In contrast, less is known about the organization of astrocytic processes at GABAergic synapses although bi-directional signaling is known to exist at these synapses too. Therefore, we established super-resolution expansion microscopy of GABAergic synapses and nearby astrocytic processes in the of the mouse hippocampal CA1 region. By visualizing the presynaptic vesicular GABA transporter and the postsynaptic clustering protein gephyrin, we documented the subsynaptic heterogeneity of GABAergic synaptic contacts. We then compared the volume distribution of astrocytic processes near GABAergic synapses between individual synapses and with glutamatergic synapses. We made two novel observations. First, astrocytic processes were more abundant at the GABAergic synapses with large postsynaptic gephyrin clusters. Second, astrocytic processes were less abundant in the vicinity of GABAergic synapses compared to glutamatergic, suggesting that the latter may be selectively approached by astrocytes. Because of the GABA transporter distribution, we also speculate that this specific arrangement enables more efficient re-uptake of GABA into presynaptic terminals.
Topics: Animals; GABA Plasma Membrane Transport Proteins; Mice; Presynaptic Terminals; Receptors, GABA-A; Synapses; gamma-Aminobutyric Acid
PubMed: 36231112
DOI: 10.3390/cells11193150 -
Neuron Jan 2021Neurons are highly polarized cells with a single axon and multiple dendrites derived from the cell body to form tightly associated pre- and postsynaptic compartments. As... (Review)
Review
Neurons are highly polarized cells with a single axon and multiple dendrites derived from the cell body to form tightly associated pre- and postsynaptic compartments. As the biosynthetic machinery is largely restricted to the somatodendritic domain, the vast majority of presynaptic components are synthesized in the neuronal soma, packaged into synaptic precursor vesicles, and actively transported along the axon to sites of presynaptic biogenesis. In contrast with the significant progress that has been made in understanding synaptic transmission and processing of information at the post-synapse, comparably little is known about the formation and dynamic remodeling of the presynaptic compartment. We review here our current understanding of the mechanisms that govern the biogenesis, transport, and assembly of the key components for presynaptic neurotransmission, discuss how alterations in presynaptic assembly may impact nervous system function or lead to disease, and outline key open questions for future research.
Topics: Animals; Humans; Neurogenesis; Presynaptic Terminals; Protein Transport; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 33098763
DOI: 10.1016/j.neuron.2020.09.038 -
Biochemical and Biophysical Research... Sep 2022The activity-dependent regulation of synaptic structures plays a key role in synaptic development and plasticity; however, the signaling mechanisms involved remain...
The activity-dependent regulation of synaptic structures plays a key role in synaptic development and plasticity; however, the signaling mechanisms involved remain largely unknown. The serine/threonine protein kinase Akt, a downstream effector of phosphoinositide 3-kinase (PI3K), plays a pivotal role in a wide range of physiological functions. We focused on the importance of Akt in rapid synaptic structural changes after stimulation at the Drosophila neuromuscular junction, a well-studied model synapse. Compared with wild-type larvae, akt mutants showed significantly reduced muscle size and an increased number of boutons per area, suggesting that Akt is required for proper pre- and postsynaptic growth. In addition, the level of cysteine string protein (CSP) was significantly increased, and its distribution was different in akt mutants. After high K single stimulation, the CSP level of akt mutant NMJs increased dramatically compared with that of wild-type NMJs. Interestingly, ghost boutons without postsynaptic specialization were found in akt mutant NMJs, and the number of these boutons was significantly increased by patterned stimulation. In contrast, the postsynaptic change in the subsynaptic reticulum (SSR) in the akt mutant occurred independent of stimulation. These results suggest that Akt functions in both pre- and postsynaptic growth and differentiation, and in particular, presynaptic action occurs in an activity-dependent manner.
Topics: Animals; Drosophila; Drosophila Proteins; Neuromuscular Junction; Phosphatidylinositol 3-Kinases; Presynaptic Terminals; Proto-Oncogene Proteins c-akt; Synaptic Transmission
PubMed: 35820284
DOI: 10.1016/j.bbrc.2022.06.093 -
Journal of Neurochemistry Apr 2021Parkinson's disease is a common neurodegenerative disorder and is clinically characterized by bradykinesia, rigidity, and resting tremor. Missense mutations in the... (Review)
Review
Parkinson's disease is a common neurodegenerative disorder and is clinically characterized by bradykinesia, rigidity, and resting tremor. Missense mutations in the leucine-rich repeat protein kinase-2 gene (LRRK2) are a recognized cause of inherited Parkinson's disease. The physiological and pathological impact of LRRK2 is still obscure, but accumulating evidence indicates that LRRK2 orchestrates diverse aspects of membrane trafficking, such as membrane fusion and vesicle formation and transport along actin and tubulin tracks. In the present review, we focus on the special relation between LRRK2 and synaptic vesicles. LRRK2 binds and phosphorylates key actors within the synaptic vesicle cycle. Accordingly, alterations in dopamine and glutamate transmission have been described upon LRRK2 manipulations. However, the different modeling strategies and phenotypes observed require a critical approach to decipher the outcome of LRRK2 at the pre-synaptic site.
Topics: Animals; Endocytosis; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Neurons; Parkinson Disease; Presynaptic Terminals; Synaptic Vesicles
PubMed: 33206398
DOI: 10.1111/jnc.15240 -
Molecular and Cellular Neurosciences Apr 2021Sound information encoding within the initial synapses in the auditory brainstem requires reliable and precise synaptic transmission in response to rapid and large... (Review)
Review
Sound information encoding within the initial synapses in the auditory brainstem requires reliable and precise synaptic transmission in response to rapid and large fluctuations in action potential (AP) firing rates. The magnitude and location of Ca entry through voltage-gated Ca channels (Ca) in the presynaptic terminal are key determinants in triggering AP-mediated release. In the mammalian central nervous system (CNS), the Ca2.1 subtype is the critical subtype for CNS function, since it is the most efficient Ca2 subtype in triggering AP-mediated synaptic vesicle (SV) release. Auditory brainstem synapses utilize Ca2.1 to sustain fast and repetitive SV release to encode sound information. Therefore, understanding the presynaptic mechanisms that control Ca2.1 localization, organization and biophysical properties are integral to understanding auditory processing. Here, we review our current knowledge about the control of presynaptic Ca2 abundance and organization in the auditory brainstem and impact on the regulation of auditory processing.
Topics: Animals; Auditory Pathways; Brain Stem; Calcium; Calcium Channels, N-Type; Evoked Potentials, Auditory, Brain Stem; Humans; Ion Channel Gating; Ion Transport; Mammals; Nerve Tissue Proteins; Presynaptic Terminals; Protein Domains; Protein Subunits; Synaptic Transmission; Synaptic Vesicles
PubMed: 33662542
DOI: 10.1016/j.mcn.2021.103609