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Physiological Reviews Oct 2023Calcium signaling underlies much of physiology. Almost all the Ca in the cytoplasm is bound to buffers, with typically only ∼1% being freely ionized at resting levels... (Review)
Review
Calcium signaling underlies much of physiology. Almost all the Ca in the cytoplasm is bound to buffers, with typically only ∼1% being freely ionized at resting levels in most cells. Physiological Ca buffers include small molecules and proteins, and experimentally Ca indicators will also buffer calcium. The chemistry of interactions between Ca and buffers determines the extent and speed of Ca binding. The physiological effects of Ca buffers are determined by the kinetics with which they bind Ca and their mobility within the cell. The degree of buffering depends on factors such as the affinity for Ca, the Ca concentration, and whether Ca ions bind cooperatively. Buffering affects both the amplitude and time course of cytoplasmic Ca signals as well as changes of Ca concentration in organelles. It can also facilitate Ca diffusion inside the cell. Ca buffering affects synaptic transmission, muscle contraction, Ca transport across epithelia, and the killing of bacteria. Saturation of buffers leads to synaptic facilitation and tetanic contraction in skeletal muscle and may play a role in inotropy in the heart. This review focuses on the link between buffer chemistry and function and how Ca buffering affects normal physiology and the consequences of changes in disease. As well as summarizing what is known, we point out the many areas where further work is required.
Topics: Humans; Calcium; Buffers; Cytoplasm; Heart; Synaptic Transmission; Calcium Signaling
PubMed: 37326298
DOI: 10.1152/physrev.00042.2022 -
Nature Oct 2023Multimodal astrocyte-neuron communications govern brain circuitry assembly and function. For example, through rapid glutamate release, astrocytes can control...
Multimodal astrocyte-neuron communications govern brain circuitry assembly and function. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca-dependent exocytosis similar to neurons. However, the existence of this mechanism has been questioned owing to inconsistent data and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes and using molecular, bioinformatic and imaging approaches, together with cell-specific genetic tools that interfere with glutamate exocytosis in vivo. By analysing existing single-cell RNA-sequencing databases and our patch-seq data, we identified nine molecularly distinct clusters of hippocampal astrocytes, among which we found a notable subpopulation that selectively expressed synaptic-like glutamate-release machinery and localized to discrete hippocampal sites. Using GluSnFR-based glutamate imaging in situ and in vivo, we identified a corresponding astrocyte subgroup that responds reliably to astrocyte-selective stimulations with subsecond glutamate release events at spatially precise hotspots, which were suppressed by astrocyte-targeted deletion of vesicular glutamate transporter 1 (VGLUT1). Furthermore, deletion of this transporter or its isoform VGLUT2 revealed specific contributions of glutamatergic astrocytes in cortico-hippocampal and nigrostriatal circuits during normal behaviour and pathological processes. By uncovering this atypical subpopulation of specialized astrocytes in the adult brain, we provide insights into the complex roles of astrocytes in central nervous system (CNS) physiology and diseases, and identify a potential therapeutic target.
Topics: Adult; Humans; Astrocytes; Central Nervous System; Glutamic Acid; Hippocampus; Neurons; Signal Transduction; Synaptic Transmission; Calcium; Exocytosis; Single-Cell Gene Expression Analysis; Vesicular Glutamate Transport Protein 1; Gene Deletion; Cerebral Cortex
PubMed: 37674083
DOI: 10.1038/s41586-023-06502-w -
Science (New York, N.Y.) Dec 2023Fast synaptic neurotransmission in the vertebrate central nervous system relies primarily on ionotropic glutamate receptors (iGluRs), which drive neuronal excitation,...
Fast synaptic neurotransmission in the vertebrate central nervous system relies primarily on ionotropic glutamate receptors (iGluRs), which drive neuronal excitation, and type A γ-aminobutyric acid receptors (GABARs), which are responsible for neuronal inhibition. However, the GluD1 receptor, an iGluR family member, is present at both excitatory and inhibitory synapses. Whether and how GluD1 activation may affect inhibitory neurotransmission is unknown. In this work, by using a combination of biochemical, structural, and functional analyses, we demonstrate that GluD1 binds GABA, a previously unknown feature of iGluRs. GluD1 activation produces long-lasting enhancement of GABAergic synaptic currents in the adult mouse hippocampus through a non-ionotropic mechanism that is dependent on trans-synaptic anchoring. The identification of GluD1 as a GABA receptor that controls inhibitory synaptic plasticity challenges the classical dichotomy between glutamatergic and GABAergic receptors.
Topics: Animals; Mice; gamma-Aminobutyric Acid; Glutamate Dehydrogenase; Hippocampus; Neuronal Plasticity; Receptors, GABA; Synapses; Synaptic Transmission; Neural Inhibition; Mice, Knockout; Racemases and Epimerases
PubMed: 38060673
DOI: 10.1126/science.adf3406 -
Neuron Aug 2023N-Methyl-D-aspartate ionotropic glutamate receptors (NMDARs) play key roles in synaptogenesis, synaptic maturation, long-term plasticity, neuronal network activity, and... (Review)
Review
N-Methyl-D-aspartate ionotropic glutamate receptors (NMDARs) play key roles in synaptogenesis, synaptic maturation, long-term plasticity, neuronal network activity, and cognition. Mirroring this wide range of instrumental functions, abnormalities in NMDAR-mediated signaling have been associated with numerous neurological and psychiatric disorders. Thus, identifying the molecular mechanisms underpinning the physiological and pathological contributions of NMDAR has been a major area of investigation. Over the past decades, a large body of literature has flourished, revealing that the physiology of ionotropic glutamate receptors cannot be restricted to fluxing ions, and involves additional facets controlling synaptic transmissions in health and disease. Here, we review newly discovered dimensions of postsynaptic NMDAR signaling supporting neural plasticity and cognition, such as the nanoscale organization of NMDAR complexes, their activity-dependent redistributions, and non-ionotropic signaling capacities. We also discuss how dysregulations of these processes may directly contribute to NMDAR-dysfunction-related brain diseases.
Topics: Humans; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synaptic Transmission; Neuronal Plasticity; Neurons
PubMed: 37236178
DOI: 10.1016/j.neuron.2023.05.002 -
FEBS Letters Sep 2023Evidence from biochemistry, genetics, and electron microscopy strongly supports the idea that a ring of Synaptotagmin is central to the clamping and release of synaptic... (Review)
Review
Evidence from biochemistry, genetics, and electron microscopy strongly supports the idea that a ring of Synaptotagmin is central to the clamping and release of synaptic vesicles (SVs) for synchronous neurotransmission. Recent direct measurements in cell-free systems suggest there are 12 SNAREpins in each ready-release vesicle, consisting of six peripheral and six central SNAREpins. The six central SNAREpins are directly bound to the Synaptotagmin ring, are directly released by Ca , and they initially open the fusion pore. The six peripheral SNAREpins are indirectly bound to the ring, each linked to a central SNAREpin by a bridging molecule of Complexin. We suggest that the primary role of peripheral SNAREpins is to provide additional force to 'turbocharge' neurotransmitter release, explaining how it can occur much faster than other forms of membrane fusion. The SV protein Synaptophysin forms hexamers that bear two copies of the v-SNARE VAMP at each vertex, one likely assembling into a peripheral SNAREpin and the other into a central SNAREpin.
Topics: Biological Transport; Cell-Free System; Head; Synaptic Transmission; Synaptotagmins
PubMed: 37643878
DOI: 10.1002/1873-3468.14718 -
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 -
Nature Neuroscience Sep 2023Social hierarchy is established as an outcome of individual social behaviors, such as dominance behavior during long-term interactions with others. Astrocytes are...
Social hierarchy is established as an outcome of individual social behaviors, such as dominance behavior during long-term interactions with others. Astrocytes are implicated in optimizing the balance between excitatory and inhibitory (E/I) neuronal activity, which may influence social behavior. However, the contribution of astrocytes in the prefrontal cortex to dominance behavior is unclear. Here we show that dorsomedial prefrontal cortical (dmPFC) astrocytes modulate E/I balance and dominance behavior in adult male mice using in vivo fiber photometry and two-photon microscopy. Optogenetic and chemogenetic activation or inhibition of dmPFC astrocytes show that astrocytes bidirectionally control male mouse dominance behavior, affecting social rank. Dominant and subordinate male mice present distinct prefrontal synaptic E/I balance, regulated by astrocyte activity. Mechanistically, we show that dmPFC astrocytes control cortical E/I balance by simultaneously enhancing presynaptic-excitatory and reducing postsynaptic-inhibitory transmission via astrocyte-derived glutamate and ATP release, respectively. Our findings show how dmPFC astrocyte-neuron communication can be involved in the establishment of social hierarchy in adult male mice.
Topics: Mice; Animals; Male; Synapses; Astrocytes; Neurons; Prefrontal Cortex; Synaptic Transmission
PubMed: 37563296
DOI: 10.1038/s41593-023-01406-4 -
Cell Metabolism Feb 2024Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through...
Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMH neurons), that regulates aging and longevity in mice. DMH neurons regulate physical activity and WAT function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation. Within DMH neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMH neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.
Topics: Mice; Animals; Longevity; Aging; Neurons; Synaptic Transmission; Adipose Tissue; Hypothalamus; Dorsomedial Hypothalamic Nucleus; Mammals; Cyclic GMP-Dependent Protein Kinase Type I
PubMed: 38194970
DOI: 10.1016/j.cmet.2023.12.011 -
Nature Neuroscience Feb 2024Neurovascular coupling (NVC) is important for brain function and its dysfunction underlies many neuropathologies. Although cell-type specificity has been implicated in...
Neurovascular coupling (NVC) is important for brain function and its dysfunction underlies many neuropathologies. Although cell-type specificity has been implicated in NVC, how active neural information is conveyed to the targeted arterioles in the brain remains poorly understood. Here, using two-photon focal optogenetics in the mouse cerebral cortex, we demonstrate that single glutamatergic axons dilate their innervating arterioles via synaptic-like transmission between neural-arteriolar smooth muscle cell junctions (NsMJs). The presynaptic parental-daughter bouton makes dual innervations on postsynaptic dendrites and on arteriolar smooth muscle cells (aSMCs), which express many types of neuromediator receptors, including a low level of glutamate NMDA receptor subunit 1 (Grin1). Disruption of NsMJ transmission by aSMC-specific knockout of GluN1 diminished optogenetic and whisker stimulation-caused functional hyperemia. Notably, the absence of GluN1 subunit in aSMCs reduced brain atrophy following cerebral ischemia by preventing Ca overload in aSMCs during arteriolar constriction caused by the ischemia-induced spreading depolarization. Our findings reveal that NsMJ transmission drives NVC and open up a new avenue for studying stroke.
Topics: Mice; Animals; Neurovascular Coupling; Vasodilation; Axons; Synaptic Transmission; Arterioles; Myocytes, Smooth Muscle
PubMed: 38168932
DOI: 10.1038/s41593-023-01515-0 -
Nature Nov 2023Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood. Dysfunction of monoaminergic...
Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood. Dysfunction of monoaminergic circuits has been implicated in various neurodegenerative and neuropsychiatric disorders. Vesicular monoamine transporters (VMATs) pack monoamines into vesicles for synaptic release and are essential to neurotransmission. VMATs are also therapeutic drug targets for a number of different conditions. Despite the importance of these transporters, the mechanisms of substrate transport and drug inhibition of VMATs have remained elusive. Here we report cryo-electron microscopy structures of the human vesicular monoamine transporter VMAT2 in complex with the antichorea drug tetrabenazine, the antihypertensive drug reserpine or the substrate serotonin. Remarkably, the two drugs use completely distinct inhibition mechanisms. Tetrabenazine binds VMAT2 in a lumen-facing conformation, locking the luminal gating lid in an occluded state to arrest the transport cycle. By contrast, reserpine binds in a cytoplasm-facing conformation, expanding the vestibule and blocking substrate access. Structural analyses of VMAT2 also reveal the conformational changes following transporter isomerization that drive substrate transport into the vesicle. These findings provide a structural framework for understanding the physiology and pharmacology of neurotransmitter packaging by synaptic vesicular transporters.
Topics: Humans; Adrenergic Uptake Inhibitors; Biological Transport; Cryoelectron Microscopy; Neurotransmitter Agents; Reserpine; Serotonin; Synaptic Transmission; Tetrabenazine; Vesicular Monoamine Transport Proteins; Substrate Specificity
PubMed: 37914936
DOI: 10.1038/s41586-023-06727-9