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Neurochemistry International Oct 2023Sex differences in the brain, encompassing variations in specific brain structures, size, cognitive function, and synaptic connections, have been identified across...
Sex differences in the brain, encompassing variations in specific brain structures, size, cognitive function, and synaptic connections, have been identified across numerous species. While previous research has explored sex differences in postsynaptic structures, synaptic plasticity, and hippocampus-dependent functions, the hippocampal presynaptic terminals remain largely uninvestigated. The hippocampus is a critical structure responsible for multiple brain functions. This study examined presynaptic differences in cultured hippocampal neurons derived from male and female mice using a combination of biochemical assays, functional analyses measuring exocytosis and endocytosis of synaptic vesicle proteins, ultrastructural analyses via electron microscopy, and presynaptic Ca-specific optical probes. Our findings revealed that female neurons exhibited a higher number of synaptic vesicles at presynaptic terminals compared to male neurons. However, no significant differences were observed in presynaptic protein expression, presynaptic terminal ultrastructure, synaptic vesicle exocytosis and endocytosis, or presynaptic Ca alterations between male and female neurons.
Topics: Mice; Female; Male; Animals; Presynaptic Terminals; Sex Characteristics; Hippocampus; Synapses; Synaptic Vesicles; Exocytosis; Cells, Cultured
PubMed: 37451344
DOI: 10.1016/j.neuint.2023.105570 -
Neddylation is required for presynaptic clustering of mGlu7 and maturation of presynaptic terminals.Experimental & Molecular Medicine Mar 2021Neddylation is a posttranslational modification in which NEDD8 is conjugated to a target substrate by cellular processes similar to those involved in ubiquitination....
Neddylation is a posttranslational modification in which NEDD8 is conjugated to a target substrate by cellular processes similar to those involved in ubiquitination. Recent studies have identified PSD-95 and cofilin as substrates for neddylation in the brain and have shown that neddylation modulates the maturation and stability of dendritic spines in developing neurons. However, the precise substrates and functional consequences of neddylation at presynaptic terminals remain elusive. Here, we provide evidence that the mGlu7 receptor is a target of neddylation in heterologous cells and rat primary cultured neurons. We found that mGlu7 neddylation is reduced by agonist treatment and is required for the clustering of mGlu7 in the presynaptic active zone. In addition, we observed that neddylation is not required for the endocytosis of mGlu7, but it facilitates the ubiquitination of mGlu7 and stabilizes mGlu7 protein expression. Finally, we demonstrate that neddylation is necessary for the maturation of excitatory presynaptic terminals, providing a key role for neddylation in synaptic function.
Topics: Animals; Animals, Newborn; Cells, Cultured; Female; NEDD8 Protein; Neurons; Presynaptic Terminals; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Synapses; Ubiquitination
PubMed: 33767338
DOI: 10.1038/s12276-021-00585-z -
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 -
The Journal of Comparative Neurology May 2022Visual pathways of the brain are organized into parallel channels that code different features of the external environment. In the current study, we investigated the...
Visual pathways of the brain are organized into parallel channels that code different features of the external environment. In the current study, we investigated the anatomical organization of parallel pathways from the superior colliculus (SC) to the pulvinar nucleus in the mouse. Virus injections placed in the ipsilateral and contralateral SC to induce the expression of different fluorescent proteins define two pulvinar zones. The lateral pulvinar (Pl) receives ipsilateral SC input and the caudal medial pulvinar (Pcm) receives bilateral SC input. To examine the ultrastructure of these projections using transmission electron microscopy, we injected the SC with viruses to induce peroxidase expression within synaptic vesicles or mitochondria. We quantitatively compared the sizes of ipsilateral and contralateral tectopulvinar terminals and their postsynaptic dendrites, as well as the sizes of the overall population of synaptic terminals and their postsynaptic dendrites in the Pl and Pcm. Our ultrastructural analysis revealed that ipsilateral tectopulvinar terminals are significantly larger than contralateral tectopulvinar terminals. In particular, the ipsilateral tectopulvinar projection includes a subset of large terminals (≥ 1 μm ) that envelop dendritic protrusions of postsynaptic dendrites. We also found that both ipsilateral and contralateral tectopulvinar terminals are significantly larger than the overall population of synaptic terminals in both the Pl and Pcm. Thus, the ipsilateral tectopulvinar projection is structurally distinct from the bilateral tectopulvinar pathway, but both tectopulvinar channels may be considered the primary or "driving" input to the Pl and Pcm.
Topics: Animals; Mice; Presynaptic Terminals; Pulvinar; Superior Colliculi; Visual Pathways
PubMed: 34636423
DOI: 10.1002/cne.25264 -
Journal of Neurochemistry Dec 2020Regulation of axonal dopamine release by local microcircuitry is at the hub of several biological processes that govern the timing and magnitude of signaling events in... (Review)
Review
Regulation of axonal dopamine release by local microcircuitry is at the hub of several biological processes that govern the timing and magnitude of signaling events in reward-related brain regions. An important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms. These processes can occur via homosynaptic mechanisms-such as presynaptic dopamine autoreceptors and dopamine transporters - as well heterosynaptic mechanisms such as retrograde signaling from postsynaptic cholinergic and dynorphin systems, among others. Additionally, modulation of dopamine release via diffusible messengers, such as nitric oxide and hydrogen peroxide, allows for various metabolic factors to quickly and efficiently regulate dopamine release and subsequent signaling. Here we review how these mechanisms work in concert to influence the timing and magnitude of striatal dopamine signaling, independent of action potential activity at the level of dopaminergic cell bodies in the midbrain, thereby providing a parallel pathway by which dopamine can be modulated. Understanding the complexities of local regulation of dopamine signaling is required for building comprehensive frameworks of how activity throughout the dopamine system is integrated to drive signaling and control behavior.
Topics: Action Potentials; Animals; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Nerve Net; Presynaptic Terminals
PubMed: 32356315
DOI: 10.1111/jnc.15034 -
Current Opinion in Neurobiology Oct 2022Sustained neurotransmission is driven by a continuous supply of synaptic vesicles to the release sites and modulated by synaptic vesicle dynamics. However, synaptic... (Review)
Review
Sustained neurotransmission is driven by a continuous supply of synaptic vesicles to the release sites and modulated by synaptic vesicle dynamics. However, synaptic vesicle dynamics in synapses remain elusive because of technical limitations. Recent advances in fluorescence imaging techniques have enabled the tracking of single synaptic vesicles in small central synapses in living neurons. Single vesicle tracking has uncovered a wealth of new information about synaptic vesicle dynamics both within and outside presynaptic terminals, showing that single vesicle tracking is an effective tool for studying synaptic vesicle dynamics. Particularly, single vesicle tracking with high spatiotemporal resolution has revealed the dependence of synaptic vesicle dynamics on the location, stages of recycling, and neuronal activity. This review summarizes the recent findings from single synaptic vesicle tracking in small central synapses and their implications in synaptic transmission and pathogenic mechanisms of neurodegenerative diseases.
Topics: Neurons; Presynaptic Terminals; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 35803103
DOI: 10.1016/j.conb.2022.102596 -
The Neuroscientist : a Review Journal... Aug 2019Deposition of amyloid plaques in limbic and associative cortices is amongst the most recognized histopathologic hallmarks of Alzheimer's disease. Despite decades of... (Review)
Review
Deposition of amyloid plaques in limbic and associative cortices is amongst the most recognized histopathologic hallmarks of Alzheimer's disease. Despite decades of research, there is a lack of consensus over the impact of plaques on neuronal function, with their role in cognitive decline and memory loss undecided. Evidence has emerged suggesting complex and localized axonal pathology around amyloid plaques, with a significant fraction of swellings and dystrophies becoming enriched with putative synaptic vesicles and presynaptic proteins normally colocalized at hotspots of transmitter release. In the absence of hallmark active zone proteins and postsynaptic receptive elements, the axonal swellings surrounding amyloid plaques have been suggested as sites for ectopic release of glutamate, which under reduced clearance can lead to elevated local excitatory drive. Throughout this review, we consider the emerging data suggestive of amyloid plaques as hotspots of compulsive glutamatergic activity. Evidence for local and long-range effects of nonsynaptic glutamate is discussed in the context of circuit dysfunctions and neurodegenerative changes of Alzheimer's disease.
Topics: Alzheimer Disease; Animals; Axons; Brain; Glutamic Acid; Humans; Plaque, Amyloid; Presynaptic Terminals
PubMed: 30051750
DOI: 10.1177/1073858418791128 -
Nature Reviews. Neuroscience Apr 2020Chemical synapses are heterogeneous junctions formed between neurons that are specialized for the conversion of electrical impulses into the exocytotic release of... (Review)
Review
Chemical synapses are heterogeneous junctions formed between neurons that are specialized for the conversion of electrical impulses into the exocytotic release of neurotransmitters. Voltage-gated Ca channels play a pivotal role in this process as they are the major conduits for the Ca ions that trigger the fusion of neurotransmitter-containing vesicles with the presynaptic membrane. Alterations in the intrinsic function of these channels and their positioning within the active zone can profoundly alter the timing and strength of synaptic output. Advances in optical and electron microscopic imaging, structural biology and molecular techniques have facilitated recent breakthroughs in our understanding of the properties of voltage-gated Ca channels that support their presynaptic functions. Here we examine the nature of these channels, how they are trafficked to and anchored within presynaptic boutons, and the mechanisms that allow them to function optimally in shaping the flow of information through neural circuits.
Topics: Animals; Calcium Channels; Humans; Presynaptic Terminals; Protein Transport; Synaptic Transmission; Synaptic Vesicles
PubMed: 32161339
DOI: 10.1038/s41583-020-0278-2