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Current Neuropharmacology 2016Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh... (Review)
Review
Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh from acetyl-CoA and choline in the cytoplasm and the vesicular acetylcholine transporter (VAChT) uptakes the neurotransmitter into synaptic vesicles. Following depolarization, ACh undergoes exocytosis reaching the synaptic cleft, where it can bind its receptors, including muscarinic and nicotinic receptors. ACh present at the synaptic cleft is promptly hydrolyzed by the enzyme acetylcholinesterase (AChE), forming acetate and choline, which is recycled into the presynaptic nerve terminal by the high-affinity choline transporter (CHT1). Cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are severely lost in Alzheimer's disease (AD). AD is the most ordinary cause of dementia affecting 25 million people worldwide. The hallmarks of the disease are the accumulation of neurofibrillary tangles and amyloid plaques. However, there is no real correlation between levels of cortical plaques and AD-related cognitive impairment. Nevertheless, synaptic loss is the principal correlate of disease progression and loss of cholinergic neurons contributes to memory and attention deficits. Thus, drugs that act on the cholinergic system represent a promising option to treat AD patients.
Topics: Acetylcholine; Alzheimer Disease; Animals; Cholinergic Agents; Cholinergic Neurons; Cholinesterase Inhibitors; Drug Delivery Systems; Humans; Receptors, Cholinergic
PubMed: 26813123
DOI: 10.2174/1570159x13666150716165726 -
Cell Aug 2016Cellular compartments that cannot be biochemically isolated are challenging to characterize. Here we demonstrate the proteomic characterization of the synaptic clefts...
Cellular compartments that cannot be biochemically isolated are challenging to characterize. Here we demonstrate the proteomic characterization of the synaptic clefts that exist at both excitatory and inhibitory synapses. Normal brain function relies on the careful balance of these opposing neural connections, and understanding how this balance is achieved relies on knowledge of their protein compositions. Using a spatially restricted enzymatic tagging strategy, we mapped the proteomes of two of the most common excitatory and inhibitory synaptic clefts in living neurons. These proteomes reveal dozens of synaptic candidates and assign numerous known synaptic proteins to a specific cleft type. The molecular differentiation of each cleft allowed us to identify Mdga2 as a potential specificity factor influencing Neuroligin-2's recruitment of presynaptic neurotransmitters at inhibitory synapses.
Topics: Animals; Antigens, CD; Cell Adhesion Molecules, Neuronal; GABAergic Neurons; Glutamic Acid; HEK293 Cells; Humans; Immunoglobulins; Membrane Glycoproteins; Mice; Nerve Tissue Proteins; Neural Cell Adhesion Molecules; Peroxidase; Proteome; Proteomics; Rats; Receptors, GABA; Recombinant Fusion Proteins; Synaptic Membranes; Thalamus
PubMed: 27565350
DOI: 10.1016/j.cell.2016.07.041 -
Current Biology : CB Nov 2014Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and...
Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and a postsynaptic target cell (e.g. neuron or muscle). Adequate synapse function is an essential prerequisite of all neuronal processing, including higher cognitive functions, such as learning and memory. At synapses, neurotransmitters (e.g. amino acids, amines, peptides, and acetylcholine) are released from synaptic vesicles into the synaptic cleft in response to action potentials. The Nobel Prize for Physiology and Medicine in 2013 was awarded to James E. Rothman, Randy W. Schekman and Thomas C. Südhof "for their discoveries of the machinery regulating vesicle traffic, a major transport system in our cells". This included crucial revelations, such as the identification of the core machinery of synaptic vesicle fusion. However, in contrast to the advances concerning the organization of the core functions of the synapse, our current understanding of the processes of synapse formation and maintenance--i.e. 'synaptogenesis'--is still somewhat fragmentary. Here, we will outline the current status and future directions of the field of synaptogenesis, primarily from the perspective of the presynaptic release site.
Topics: Biological Transport; Models, Biological; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 25458214
DOI: 10.1016/j.cub.2014.10.024 -
Neuropsychiatric Disease and Treatment 2023A distinct pathology for autism spectrum disorder (ASD) remains elusive. Human and animal studies have focused on investigating the role of neurons in ASD. However,... (Review)
Review
A distinct pathology for autism spectrum disorder (ASD) remains elusive. Human and animal studies have focused on investigating the role of neurons in ASD. However, recent studies have hinted that glial cell pathology could be a characteristic of ASD. Astrocytes are the most abundant glial cell in the brain and play an important role in neuronal function, both during development and in adult. They regulate neuronal migration, dendritic and spine development, and control the concentration of neurotransmitters at the synaptic cleft. They are also responsible for synaptogenesis, synaptic development, and synaptic function. Therefore, any change in astrocyte number and/or function could contribute to the impairment of connectivity that has been reported in ASD. Data available to date is scarce but indicates that while the number of astrocytes is reduced, their state of activation and their GFAP expression is increased in ASD. Disruption of astrocyte function in ASD may affect proper neurotransmitter metabolism, synaptogenesis, and the state of brain inflammation. Astrocytes alterations are common to ASD and other neurodevelopmental disorders. Future studies about the role of astrocytes in ASD are required to better understand this disorder.
PubMed: 37077706
DOI: 10.2147/NDT.S390053 -
Current Opinion in Structural Biology Feb 2019Here, we review recent insights into the neuronal presynaptic fusion machinery that releases neurotransmitter molecules into the synaptic cleft upon stimulation. The... (Review)
Review
Here, we review recent insights into the neuronal presynaptic fusion machinery that releases neurotransmitter molecules into the synaptic cleft upon stimulation. The structure of the pre-fusion state of the SNARE/complexin-1/synaptotagmin-1 synaptic protein complex suggests a new model for the initiation of fast Ca-triggered membrane fusion. Functional studies have revealed roles of the essential factors Munc18 and Munc13, demonstrating that a part of their function involves the proper assembly of synaptic protein complexes. Near-atomic resolution structures of the NSF/αSNAP/SNARE complex provide first glimpses of the molecular machinery that disassembles the SNARE complex during the synaptic vesicle cycle. These structures show how this machinery captures the SNARE substrate and provide clues as to a possible processing mechanism.
Topics: Animals; Calcium; Humans; SNARE Proteins; Synapses; Synaptic Vesicles
PubMed: 30986753
DOI: 10.1016/j.sbi.2019.03.007