-
Molecular Psychiatry Jan 2023Major depressive disorder (MDD) is a psychiatric disease of still poorly understood molecular etiology. Extensive studies at different molecular levels point to a high... (Review)
Review
Major depressive disorder (MDD) is a psychiatric disease of still poorly understood molecular etiology. Extensive studies at different molecular levels point to a high complexity of numerous interrelated pathways as the underpinnings of depression. Major systems under consideration include monoamines, stress, neurotrophins and neurogenesis, excitatory and inhibitory neurotransmission, mitochondrial dysfunction, (epi)genetics, inflammation, the opioid system, myelination, and the gut-brain axis, among others. This review aims at illustrating how these multiple signaling pathways and systems may interact to provide a more comprehensive view of MDD's neurobiology. In particular, considering the pattern of synaptic activity as the closest physical representation of mood, emotion, and conscience we can conceptualize, each pathway or molecular system will be scrutinized for links to synaptic neurotransmission. Models of the neurobiology of MDD will be discussed as well as future actions to improve the understanding of the disease and treatment options.
Topics: Humans; Depressive Disorder, Major; Synapses; Synaptic Transmission; Inflammation; Signal Transduction
PubMed: 36203007
DOI: 10.1038/s41380-022-01806-1 -
Experimental & Molecular Medicine Apr 2018Inhibitory neurotransmission plays a key role in anxiety disorders, as evidenced by the anxiolytic effect of the benzodiazepine class of γ-aminobutyric acid (GABA)... (Review)
Review
Inhibitory neurotransmission plays a key role in anxiety disorders, as evidenced by the anxiolytic effect of the benzodiazepine class of γ-aminobutyric acid (GABA) receptor agonists and the recent discovery of anxiety-associated variants in the molecular components of inhibitory synapses. Accordingly, substantial interest has focused on understanding how inhibitory neurons and synapses contribute to the circuitry underlying adaptive and pathological anxiety behaviors. A key element of the anxiety circuitry is the amygdala, which integrates information from cortical and thalamic sensory inputs to generate fear and anxiety-related behavioral outputs. Information processing within the amygdala is heavily dependent on inhibitory control, although the specific mechanisms by which amygdala GABAergic neurons and synapses regulate anxiety-related behaviors are only beginning to be uncovered. Here, we summarize the current state of knowledge and highlight open questions regarding the role of inhibition in the amygdala anxiety circuitry. We discuss the inhibitory neuron subtypes that contribute to the processing of anxiety information in the basolateral and central amygdala, as well as the molecular determinants, such as GABA receptors and synapse organizer proteins, that shape inhibitory synaptic transmission within the anxiety circuitry. Finally, we conclude with an overview of current and future approaches for converting this knowledge into successful treatment strategies for anxiety disorders.
Topics: Amygdala; Animals; Anxiety; Biomarkers; Disease Models, Animal; GABAergic Neurons; Humans; Molecular Targeted Therapy; Neurons; Receptors, GABA; Signal Transduction; Synapses; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 29628509
DOI: 10.1038/s12276-018-0063-8 -
Cell Jul 2021Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of...
Microglia, the resident immune cells of the brain, have emerged as crucial regulators of synaptic refinement and brain wiring. However, whether the remodeling of distinct synapse types during development is mediated by specialized microglia is unknown. Here, we show that GABA-receptive microglia selectively interact with inhibitory cortical synapses during a critical window of mouse postnatal development. GABA initiates a transcriptional synapse remodeling program within these specialized microglia, which in turn sculpt inhibitory connectivity without impacting excitatory synapses. Ablation of GABA receptors within microglia impairs this process and leads to behavioral abnormalities. These findings demonstrate that brain wiring relies on the selective communication between matched neuronal and glial cell types.
Topics: Animals; Animals, Newborn; Behavior, Animal; Gene Expression Regulation; HEK293 Cells; Humans; Mice; Microglia; Neural Inhibition; Parvalbumins; Phenotype; Receptors, GABA-B; Synapses; Transcription, Genetic; gamma-Aminobutyric Acid
PubMed: 34233165
DOI: 10.1016/j.cell.2021.06.018 -
Nature Aging Sep 2022Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial...
Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in Tau hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in Tau mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.
Topics: Mice; Animals; Alzheimer Disease; Complement C1q; Microglia; Astrocytes; Synapses; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37118504
DOI: 10.1038/s43587-022-00281-1 -
Nature Dec 2020Perisynaptic astrocytic processes are an integral part of central nervous system synapses; however, the molecular mechanisms that govern astrocyte-synapse adhesions and...
Perisynaptic astrocytic processes are an integral part of central nervous system synapses; however, the molecular mechanisms that govern astrocyte-synapse adhesions and how astrocyte contacts control synapse formation and function are largely unknown. Here we use an in vivo chemico-genetic approach that applies a cell-surface fragment complementation strategy, Split-TurboID, and identify a proteome that is enriched at astrocyte-neuron junctions in vivo, which includes neuronal cell adhesion molecule (NRCAM). We find that NRCAM is expressed in cortical astrocytes, localizes to perisynaptic contacts and is required to restrict neuropil infiltration by astrocytic processes. Furthermore, we show that astrocytic NRCAM interacts transcellularly with neuronal NRCAM coupled to gephyrin at inhibitory postsynapses. Depletion of astrocytic NRCAM reduces numbers of inhibitory synapses without altering glutamatergic synaptic density. Moreover, loss of astrocytic NRCAM markedly decreases inhibitory synaptic function, with minor effects on excitation. Thus, our results present a proteomic framework for how astrocytes interface with neurons and reveal how astrocytes control GABAergic synapse formation and function.
Topics: Animals; Astrocytes; Cell Adhesion Molecules, Neuronal; Cell Shape; Female; GABAergic Neurons; Genetic Complementation Test; HEK293 Cells; Humans; Male; Mice; Neural Inhibition; Neurons; Proteome; Proteomics; Synapses; gamma-Aminobutyric Acid
PubMed: 33177716
DOI: 10.1038/s41586-020-2926-0 -
Cell Nov 2023Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, the diversity...
Neurons build synaptic contacts using different protein combinations that define the specificity, function, and plasticity potential of synapses; however, the diversity of synaptic proteomes remains largely unexplored. We prepared synaptosomes from 7 different transgenic mouse lines with fluorescently labeled presynaptic terminals. Combining microdissection of 5 different brain regions with fluorescent-activated synaptosome sorting (FASS), we isolated and analyzed the proteomes of 18 different synapse types. We discovered ∼1,800 unique synapse-type-enriched proteins and allocated thousands of proteins to different types of synapses (https://syndive.org/). We identify shared synaptic protein modules and highlight the proteomic hotspots for synapse specialization. We reveal unique and common features of the striatal dopaminergic proteome and discover the proteome signatures that relate to the functional properties of different interneuron classes. This study provides a molecular systems-biology analysis of synapses and a framework to integrate proteomic information for synapse subtypes of interest with cellular or circuit-level experiments.
Topics: Animals; Mice; Brain; Mice, Transgenic; Proteome; Proteomics; Synapses; Synaptosomes
PubMed: 37918396
DOI: 10.1016/j.cell.2023.09.028 -
Journal of Integrative Neuroscience Jun 2022The cellular, molecular and physiological basis of cognition has proved elusive until emerging studies on astrocytes. The appearance of a deliberate aggregating element... (Review)
Review
The cellular, molecular and physiological basis of cognition has proved elusive until emerging studies on astrocytes. The appearance of a deliberate aggregating element in cellular neurophysiology was difficult to satisfy computationally with excitatory and inhibitory neuron physiology alone. Similarly, the complex behavioral outputs of cognition are challenging to test experimentally. Astrocytic reception and control of synaptic communication has provided the possibility for study of the missing element. The advancement of genetic and neurophysiological techniques have now demonstrated astrocytes respond to neural input and subsequently provide the ability for neural synchronization and assembly at multiple and single synaptic levels. Considering the most recent evidence, it is becoming clear that astrocytes contribute to cognition. Is it possible then that our cognitive experience is essentially the domain of astrocyte physiology, ruminating on neural input, and controlling neural output? Although the molecular and cellular complexities of cognition in the human nervous system cannot be overstated, in order to gain a better understanding of the current evidence, an astrocyte centric basis of cognition will be considered from a philosophical, biological and computational perspective.
Topics: Astrocytes; Cognition; Humans; Neurons; Synapses
PubMed: 35864764
DOI: 10.31083/j.jin2104112 -
Cell Jun 2023Animals with complex nervous systems demand sleep for memory consolidation and synaptic remodeling. Here, we show that, although the Caenorhabditis elegans nervous...
Animals with complex nervous systems demand sleep for memory consolidation and synaptic remodeling. Here, we show that, although the Caenorhabditis elegans nervous system has a limited number of neurons, sleep is necessary for both processes. In addition, it is unclear if, in any system, sleep collaborates with experience to alter synapses between specific neurons and whether this ultimately affects behavior. C. elegans neurons have defined connections and well-described contributions to behavior. We show that spaced odor-training and post-training sleep induce long-term memory. Memory consolidation, but not acquisition, requires a pair of interneurons, the AIYs, which play a role in odor-seeking behavior. In worms that consolidate memory, both sleep and odor conditioning are required to diminish inhibitory synaptic connections between the AWC chemosensory neurons and the AIYs. Thus, we demonstrate in a living organism that sleep is required for events immediately after training that drive memory consolidation and alter synaptic structures.
Topics: Animals; Odorants; Caenorhabditis elegans; Smell; Sleep; Synapses
PubMed: 37269832
DOI: 10.1016/j.cell.2023.05.006 -
Cell Aug 2018Synapses are semi-membraneless, protein-dense, sub-micron chemical reaction compartments responsible for signal processing in each and every neuron. Proper formation and...
Synapses are semi-membraneless, protein-dense, sub-micron chemical reaction compartments responsible for signal processing in each and every neuron. Proper formation and dynamic responses to stimulations of synapses, both during development and in adult, are fundamental to functions of mammalian brains, although the molecular basis governing formation and modulation of compartmentalized synaptic assemblies is unclear. Here, we used a biochemical reconstitution approach to show that, both in solution and on supported membrane bilayers, multivalent interaction networks formed by major excitatory postsynaptic density (PSD) scaffold proteins led to formation of PSD-like assemblies via phase separation. The reconstituted PSD-like assemblies can cluster receptors, selectively concentrate enzymes, promote actin bundle formation, and expel inhibitory postsynaptic proteins. Additionally, the condensed phase PSD assemblies have features that are distinct from those in homogeneous solutions and fit for synaptic functions. Thus, we have built a molecular platform for understanding how neuronal synapses are formed and dynamically regulated.
Topics: Animals; Brain; Disks Large Homolog 4 Protein; Hippocampus; Light; Mice; Microscopy, Confocal; Neurogenesis; Neuronal Plasticity; Neurons; Post-Synaptic Density; Scattering, Radiation; Signal Transduction; Synapses; Synaptic Transmission
PubMed: 30078712
DOI: 10.1016/j.cell.2018.06.047 -
Science (New York, N.Y.) Jan 2019How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of...
How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.
Topics: Animals; Cerebral Cortex; Dendrites; Gene Expression Regulation, Developmental; Interneurons; Mice; Pyramidal Cells; Sequence Analysis, RNA; Synapses; Transcription, Genetic; Transcriptome
PubMed: 30679375
DOI: 10.1126/science.aau8977