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Science (New York, N.Y.) Mar 2024The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells and dendrites of CA3 pyramidal neurons, is a key synapse in the trisynaptic... (Review)
Review
The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells and dendrites of CA3 pyramidal neurons, is a key synapse in the trisynaptic circuitry of the hippocampus. Because of its comparatively large size, this synapse is accessible to direct presynaptic recording, allowing a rigorous investigation of the biophysical mechanisms of synaptic transmission and plasticity. Furthermore, because of its placement in the very center of the hippocampal memory circuit, this synapse seems to be critically involved in several higher network functions, such as learning, memory, pattern separation, and pattern completion. Recent work based on new technologies in both nanoanatomy and nanophysiology, including presynaptic patch-clamp recording, paired recording, super-resolution light microscopy, and freeze-fracture and "flash-and-freeze" electron microscopy, has provided new insights into the structure, biophysics, and network function of this intriguing synapse. This brings us one step closer to answering a fundamental question in neuroscience: how basic synaptic properties shape higher network computations.
Topics: Mossy Fibers, Hippocampal; Presynaptic Terminals; Synaptic Transmission; CA3 Region, Hippocampal; Pyramidal Cells; Humans; Animals
PubMed: 38452088
DOI: 10.1126/science.adg6757 -
Cell Reports Mar 2024We examined the distribution of pre-synaptic contacts in axons of mouse neurons and constructed whole-brain single-cell neuronal networks using an extensive dataset of...
We examined the distribution of pre-synaptic contacts in axons of mouse neurons and constructed whole-brain single-cell neuronal networks using an extensive dataset of 1,891 fully reconstructed neurons. We found that bouton locations were not homogeneous throughout the axon and among brain regions. As our algorithm was able to generate whole-brain single-cell connectivity matrices from full morphology reconstruction datasets, we further found that non-homogeneous bouton locations have a significant impact on network wiring, including degree distribution, triad census, and community structure. By perturbing neuronal morphology, we further explored the link between anatomical details and network topology. In our in silico exploration, we found that dendritic and axonal tree span would have the greatest impact on network wiring, followed by synaptic contact deletion. Our results suggest that neuroanatomical details must be carefully addressed in studies of whole-brain networks at the single-cell level.
Topics: Animals; Mice; Axons; Brain; Neurons; Presynaptic Terminals
PubMed: 38451816
DOI: 10.1016/j.celrep.2024.113871 -
Nature Communications Mar 2024How sensory systems extract salient features from natural environments and organize them across neural pathways is unclear. Combining single-cell and population...
How sensory systems extract salient features from natural environments and organize them across neural pathways is unclear. Combining single-cell and population two-photon calcium imaging in mice, we discover that retinal ON bipolar cells (second-order neurons of the visual system) are divided into two blocks of four types. The two blocks distribute temporal and spatial information encoding, respectively. ON bipolar cell axons co-stratify within each block, but separate laminarly between them (upper block: diverse temporal, uniform spatial tuning; lower block: diverse spatial, uniform temporal tuning). ON bipolar cells extract temporal and spatial features similarly from artificial and naturalistic stimuli. In addition, they differ in sensitivity to coherent motion in naturalistic movies. Motion information is distributed across ON bipolar cells in the upper and the lower blocks, multiplexed with temporal and spatial contrast, independent features of natural scenes. Comparing the responses of different boutons within the same arbor, we find that axons of all ON bipolar cell types function as computational units. Thus, our results provide insights into the visual feature extraction from naturalistic stimuli and reveal how structural and functional organization cooperate to generate parallel ON pathways for temporal and spatial information in the mammalian retina.
Topics: Animals; Mice; Retina; Retinal Bipolar Cells; Axons; Presynaptic Terminals; Mammals
PubMed: 38429280
DOI: 10.1038/s41467-024-46348-y -
Proceedings of the National Academy of... Mar 2024
Topics: Synaptic Vesicles; Receptors, GABA-B; Habenula; Neuronal Plasticity; Presynaptic Terminals; gamma-Aminobutyric Acid
PubMed: 38422062
DOI: 10.1073/pnas.2401734121 -
Nature Mar 2024Astrocytes are heterogeneous glial cells of the central nervous system. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour...
Astrocytes are heterogeneous glial cells of the central nervous system. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. Here we show that a specific population of astrocytes in the central striatum expresses μ-crystallin (encoded by Crym in mice and CRYM in humans) that is associated with several human diseases, including neuropsychiatric disorders. In adult mice, reducing the levels of μ-crystallin in striatal astrocytes through CRISPR-Cas9-mediated knockout of Crym resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory-inhibitory synaptic balance. Increased perseveration stemmed from the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics, and that this treatment also corrected the synaptic deficits. Together, our findings reveal converging molecular, synaptic, circuit and behavioural mechanisms by which a molecularly defined and allocated population of striatal astrocytes gates perseveration phenotypes that accompany neuropsychiatric disorders. Our data show that Crym-positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte-neuron interaction mechanisms that could be targeted in treatments for perseveration.
Topics: Animals; Humans; Mice; Astrocytes; Corpus Striatum; Gene Editing; Gene Knockout Techniques; mu-Crystallins; Rumination, Cognitive; Synaptic Transmission; CRISPR-Cas Systems; Medium Spiny Neurons; Synapses; Prefrontal Cortex; Presynaptic Terminals; Neural Inhibition
PubMed: 38418885
DOI: 10.1038/s41586-024-07138-0 -
The European Journal of Neuroscience May 2024The small ventrolateral neurons (sLNvs) are key components of the central clock in the Drosophila brain. They signal via the neuropeptide pigment-dispersing factor (PDF)...
The small ventrolateral neurons (sLNvs) are key components of the central clock in the Drosophila brain. They signal via the neuropeptide pigment-dispersing factor (PDF) to align the molecular clockwork of different central clock neurons and to modulate downstream circuits. The dorsal terminals of the sLNvs undergo daily morphological changes that affect presynaptic sites organised by the active zone protein Bruchpilot (BRP), a homolog of mammalian ELKS proteins. However, the role of these presynaptic sites for PDF release is ill-defined. Here, we combined expansion microscopy with labelling of active zones by endogenously tagged BRP to examine the spatial correlation between PDF-containing dense-core vesicles and BRP-labelled active zones. We found that the number of BRP-labelled puncta in the sLNv terminals was similar while their density differed between Zeitgeber time (ZT) 2 and 14. The relative distance between BRP- and PDF-labelled puncta was increased in the morning, around the reported time of PDF release. Spontaneous dense-core vesicle release profiles of sLNvs in a publicly available ssTEM dataset (FAFB) consistently lacked spatial correlation to BRP-organised active zones. RNAi-mediated downregulation of brp and other active zone proteins expressed by the sLNvs did not affect PDF-dependent locomotor rhythmicity. In contrast, down-regulation of genes encoding proteins of the canonical vesicle release machinery, the dense-core vesicle-related protein CADPS, as well as PDF impaired locomotor rhythmicity. Taken together, our study suggests that PDF release from the sLNvs is independent of BRP-organised active zones, while BRP may be redistributed to active zones in a time-dependent manner.
Topics: Animals; Drosophila Proteins; Neuropeptides; Neurons; Drosophila; Presynaptic Terminals; Circadian Rhythm; Brain; Drosophila melanogaster; Signal Transduction
PubMed: 38414155
DOI: 10.1111/ejn.16294 -
Cells Feb 2024Glutamate receptors at the postsynaptic side translate neurotransmitter release from presynapses into postsynaptic excitation. They play a role in many forms of synaptic...
Glutamate receptors at the postsynaptic side translate neurotransmitter release from presynapses into postsynaptic excitation. They play a role in many forms of synaptic plasticity, e.g., homeostatic scaling of the receptor field, activity-dependent synaptic plasticity and the induction of presynaptic homeostatic potentiation (PHP). The latter process has been extensively studied at neuromuscular junctions (NMJs). The genetic removal of the glutamate receptor subunit IIA (GluRIIA) leads to an induction of PHP at the synapse. So far, mostly imprecise knockouts of the gene have been utilized. Furthermore, mutated and tagged versions of GluRIIA have been examined in the past, but most of these constructs were not expressed under endogenous regulatory control or involved the mentioned imprecise knockouts. We performed CRISPR/Cas9-assisted gene editing at the endogenous locus of . This enabled the investigation of the endogenous expression pattern of GluRIIA using tagged constructs with an EGFP and an ALFA tag for super-resolution immunofluorescence imaging, including structured illumination microscopy (SIM) and stochastic optical reconstruction microscopy (STORM). All GluRIIA constructs exhibited full functionality and PHP could be induced by philanthotoxin at control levels. By applying hierarchical clustering algorithms to analyze the STORM data, we detected postsynaptic receptor cluster areas of ~0.15 µm. Consequently, our constructs are suitable for ultrastructural analyses of GluRIIA.
Topics: Animals; Carrier Proteins; Drosophila melanogaster; Drosophila Proteins; Neuromuscular Junction; Presynaptic Terminals; Synapses; Receptors, Ionotropic Glutamate
PubMed: 38391936
DOI: 10.3390/cells13040323 -
The Journal of Neuroscience : the... May 2024Synapses maintain two forms of neurotransmitter release to support communication in the brain. First, evoked neurotransmitter release is triggered by the invasion of an...
Synapses maintain two forms of neurotransmitter release to support communication in the brain. First, evoked neurotransmitter release is triggered by the invasion of an action potential (AP) across en passant boutons that form along axons. The probability of evoked release () varies substantially across boutons, even within a single axon. Such heterogeneity is the result of differences in the probability of a single synaptic vesicle (SV) fusing (Pv) and in the number of vesicles available for immediate release, known as the readily releasable pool (RRP). Spontaneous release (also known as a mini) is an important form of neurotransmission that occurs in the absence of APs. Because it cannot be triggered with electrical stimulation, much less is known about potential heterogeneity in the frequency of spontaneous release between boutons. We utilized a photostable and bright fluorescent indicator of glutamate release (iGluSnFR3) to quantify both spontaneous and evoked release at individual glutamatergic boutons. We found that the rate of spontaneous release is quite heterogenous at the level of individual boutons. Interestingly, when measuring both evoked and spontaneous release at single synapses, we found that boutons with the highest rates of spontaneous release also displayed the largest evoked responses. Using a new optical method to measure RRP at individual boutons, we found that this heterogeneity in spontaneous release was strongly correlated with the size of the RRP, but not related to Pv. We conclude that the RRP is a critical and dynamic aspect of synaptic strength that contributes to both evoked and spontaneous vesicle release.
Topics: Synaptic Vesicles; Animals; Synaptic Transmission; Presynaptic Terminals; Male; Rats; Female; Glutamic Acid; Mice; Rats, Sprague-Dawley
PubMed: 38383495
DOI: 10.1523/JNEUROSCI.1253-23.2024 -
Neuropsychopharmacology : Official... May 2024In the central nervous system, noradrenaline transmission controls the degree to which we are awake, alert, and attentive. Aberrant noradrenaline transmission is...
In the central nervous system, noradrenaline transmission controls the degree to which we are awake, alert, and attentive. Aberrant noradrenaline transmission is associated with pathological forms of hyper- and hypo-arousal that present in numerous neuropsychiatric disorders often associated with dysfunction in serotonin transmission. In vivo, noradrenaline regulates the release of serotonin because noradrenergic input drives the serotonin neurons to fire action potentials via activation of excitatory α1-adrenergic receptors (α1-A). Despite the critical influence of noradrenaline on the activity of dorsal raphe serotonin neurons, the source of noradrenergic afferents has not been resolved and the presynaptic mechanisms that regulate noradrenaline-dependent synaptic transmission have not been described. Using an acute brain slice preparation from male and female mice and electrophysiological recordings from dorsal raphe serotonin neurons, we found that selective optogenetic activation of locus coeruleus terminals in the dorsal raphe was sufficient to produce an α1-A-mediated excitatory postsynaptic current (α1-A-EPSC). Activation of inhibitory α2-adrenergic receptors (α2-A) with UK-14,304 eliminated the α1-A-EPSC via presynaptic inhibition of noradrenaline release, likely via inhibition of voltage-gated calcium channels. In a subset of serotonin neurons, activation of postsynaptic α2-A produced an outward current through activation of GIRK potassium conductance. Further, in vivo activation of α2-A by systemic administration of clonidine reduced the expression of c-fos in the dorsal raphe serotonin neurons, indicating reduced neural activity. Thus, α2-A are critical regulators of serotonin neuron excitability.
Topics: Animals; Dorsal Raphe Nucleus; Male; Receptors, Adrenergic, alpha-2; Locus Coeruleus; Female; Serotonergic Neurons; Synaptic Transmission; Mice; Excitatory Postsynaptic Potentials; Optogenetics; Adrenergic alpha-2 Receptor Agonists; Mice, Inbred C57BL; Norepinephrine; Mice, Transgenic
PubMed: 38368493
DOI: 10.1038/s41386-024-01824-3 -
ENeuro Mar 2024Dopamine neurons switch from tonic pacemaker activity to high-frequency bursts in response to salient stimuli. These bursts lead to superlinear increases in dopamine...
Dopamine neurons switch from tonic pacemaker activity to high-frequency bursts in response to salient stimuli. These bursts lead to superlinear increases in dopamine release, and the degree of this increase is highly dependent on firing frequency. The superlinearity and frequency dependence of dopamine release implicate short-term plasticity processes. The presynaptic Ca-sensor synaptotagmin-7 (SYT7) has suitable properties to mediate such short-term plasticity and has been implicated in regulating dopamine release from somatodendritic compartments. Here, we use a genetically encoded dopamine sensor and whole-cell electrophysiology in KO mice to determine how SYT7 contributes to both axonal and somatodendritic dopamine release. We find that SYT7 mediates a hidden component of facilitation of release from dopamine terminals that can be unmasked by lowering initial release probability or by predepressing synapses with low-frequency stimulation. Depletion of SYT7 increased short-term depression and reduced release during stimulations that mimic in vivo firing. Recordings of D2-mediated inhibitory postsynaptic currents in the substantia nigra pars compacta (SNc) confirmed a similar role for SYT7 in somatodendritic release. Our results indicate that SYT7 drives short-term facilitation of dopamine release, which may explain the frequency dependence of dopamine signaling seen in vivo.
Topics: Animals; Mice; Calcium; Depression; Dopamine; Dopaminergic Neurons; Synapses; Synaptotagmins
PubMed: 38365841
DOI: 10.1523/ENEURO.0501-23.2024