Synapses and Neurotransmission

Synapses

Anatomy of the synapse

In the CNS, a synapse is a structural part of a neuron that passes an electrical or chemical signal to another neuron or to a target cell.

Neuron structure:

• Cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane
• Cell body (soma)
• Dendrites Dendrites Extensions of the nerve cell body. They are short and branched and receive stimuli from other neurons. Nervous System: Histology
• Axon
• Myelin sheath
• Nodes of Ranvier (between myelin sheaths)
• Synapse

At a synapse:

• A signal-passing neuron (the presynaptic neuron) 
• The target neuron (the postsynaptic neuron)
• The 2 membranes create a synaptic cleft that carries out the signaling process (neurotransmission)

Synapses by location

• Axodendritic: axon to a dendrite
• Axosomatic: axon to a soma
• Axosecretory: axon to a blood vessel
• Axoaxonic: axon to another axon
• Dendrodendritic: dendrite to another dendrite
• Axoextracellular: axon with no connection

Types of synapses

Electrical synapses:

• Gap with channel proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis connecting 2 neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology so that an electrical signal can travel over the synapse.
• 2 neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology connected through special channels Channels The Cell: Cell Membrane called gap junctions Gap Junctions Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. The Cell: Cell Junctions 
• Unregulated
• Allow signals to be transferred rapidly between cells
• Found in specialized locations:
  • Heart
  • Smooth muscle
  • Pulp of the tooth
  • Retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy of the eye

Chemical synapses:

• Gap between 2 neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology where information passes chemically in the form of neurotransmitter molecules
• Contains:
  • Presynaptic membrane
  • Synaptic cleft
  • Postsynaptic membrane
• Most common chemical synapse:
  • Neuromuscular junction Neuromuscular junction The synapse between a neuron and a muscle. Skeletal Muscle Contraction 
  • Formed by the contact between a motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology neuron and a muscle fiber
• Postsynaptic conductance or postsynaptic potentials (PSPs)
  • Excitatory postsynaptic potentials (EPSPs): PSPs that ↑ the likelihood of a postsynaptic action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential occurring
  • Inhibitory postsynaptic potentials (IPSPs): PSPs that ↓ the likelihood of a postsynaptic action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential occurring
  • Whether a postsynaptic response is an EPSP or an IPSP depends on:
    • The type of channel that is coupled to the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors.
    • The concentration of permanent ions inside and outside the cell.

Neurotransmitters

> 500 unique neurotransmitters have been identified in humans. Neurotransmitters are:

• Proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis stored in the synaptic vesicles Vesicles Female Genitourinary Examination
• Chemical messengers that transmit signals from a neuron to a target cell
• Clustered close to the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane of the axon terminal
• Released into the synaptic cleft as a result of a threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential in the presynaptic neuron
• Either excitatory or inhibitory

Neurotransmitter classes

• Amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids:
  • Glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids
  • Glycine Glycine A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. Synthesis of Nonessential Amino Acids
  • GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS
• Cholinergic:
  • Acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS
• Catecholamine:
  • Dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS
  • Norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS
  • Epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs
• Monoamine:
  • Serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS
  • Histamine
• Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation:
  • Dynorphins Dynorphins A class of opioid peptides including dynorphin a, dynorphin b, and smaller fragments of these peptides. Dynorphins prefer kappa-opioid receptors and have been shown to play a role as central nervous system transmitters. Receptors and Neurotransmitters of the CNS
  • Endorphins Endorphins One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. Receptors and Neurotransmitters of the CNS
  • Enkephalins Enkephalins One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. Receptors and Neurotransmitters of the CNS
• Soluble gases:
  • NO
  • CO

Common neurotransmitters and their actions

Neurotransmission

1. Vesicles Vesicles Female Genitourinary Examination filled with neurotransmitters are manufactured in the cell soma and transported to and stored in the presynaptic knob.
2. Action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential arrives via the axon.
3. Voltage-gated Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ channels Channels The Cell: Cell Membrane open.
4. Vesicles Vesicles Female Genitourinary Examination are stimulated.
5. Neurotransmitter vesicles Vesicles Female Genitourinary Examination fuse with synaptic membranes and release the neurotransmitter contents in the synaptic cleft.
6. Postsynaptic receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors binds the transmitter and opens. 
7. Unbound transmitter is degraded, recycled, or diffused out of the cleft.

Clinical Relevance

• Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis: autoimmune disease characterized by a production of autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques against acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors on the postsynaptic membrane. When these receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors are blocked, muscle contraction is inhibited. Individuals with myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis report exhaustion and fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia. The classic early symptom is drooping of the eyelids Eyelids Each of the upper and lower folds of skin which cover the eye when closed. Blepharitis as nighttime approaches.
• Parkinson’s disease: neurodegenerative disorder in which the production of dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS is decreased owing to destruction of the cells producing it in the substantia nigra Substantia nigra The black substance in the ventral midbrain or the nucleus of cells containing the black substance. These cells produce dopamine, an important neurotransmitter in regulation of the sensorimotor system and mood. The dark colored melanin is a by-product of dopamine synthesis. Basal Ganglia: Anatomy. This destruction results in symptoms such as tremors, loss of movement control, hypokinesia, rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon, dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders, and depression.
• Tetanus toxin Tetanus Toxin Protein synthesized by Clostridium tetani as a single chain of ~150 kda with 35% sequence identity to botulinum toxin that is cleaved to a light and a heavy chain that are linked by a single disulfide bond. Tetanolysin is the hemolytic and tetanospasmin is the neurotoxic principle. The toxin causes disruption of the inhibitory mechanisms of the CNS, thus permitting uncontrolled nervous activity, leading to fatal convulsions. Tetanus: prevents the release of GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS, an inhibitory neurotransmitter. This release results in unchecked excitatory signals to the skeletal muscles Skeletal muscles A subtype of striated muscle, attached by tendons to the skeleton. Skeletal muscles are innervated and their movement can be consciously controlled. They are also called voluntary muscles. Muscle Tissue: Histology, which go into spasm. The jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint: Anatomy muscles are specifically affected, giving the classic sign of lockjaw Lockjaw Spasmodic contraction of the masseter muscle resulting in forceful jaw closure. This may be seen with a variety of diseases, including tetanus, as a complication of radiation therapy, trauma, or in association with neoplastic conditions. Tetanus. As the disease progresses, the respiratory muscles also get involved, causing death.
• Botulism Botulism Botulism is a rare, neuroparalytic syndrome caused by Clostridium botulinum (C. botulinum). A fatal neurotoxin (botulinum toxin) is released causing varying degrees of muscle paralysis and distinct clinical syndromes. The most common types of botulism are foodborne and infant. Botulism: Botulinum toxin Botulinum toxin Toxic proteins produced from the species Clostridium botulinum. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon endocytosis into presynaptic nerve endings. Once inside the cell the botulinum toxin light chain cleaves specific snare proteins which are essential for secretion of acetylcholine by synaptic vesicles. This inhibition of acetylcholine release results in muscular paralysis. Botulism is among the most toxic proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis known. This toxin is produced by the bacterium Clostridium botulinum Clostridium botulinum A species of anaerobic, gram-positive, rod-shaped bacteria in the family clostridiaceae that produces proteins with characteristic neurotoxicity. It is the etiologic agent of botulism in humans, wild fowl, horses; and cattle. Seven subtypes (sometimes called antigenic types, or strains) exist, each producing a different botulinum toxin (botulinum toxins). The organism and its spores are widely distributed in nature. Clostridia. When botulinum toxin Botulinum toxin Toxic proteins produced from the species Clostridium botulinum. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon endocytosis into presynaptic nerve endings. Once inside the cell the botulinum toxin light chain cleaves specific snare proteins which are essential for secretion of acetylcholine by synaptic vesicles. This inhibition of acetylcholine release results in muscular paralysis. Botulism binds to the synaptic vesicle Vesicle Primary Skin Lesions proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis and gangliosides, it prevents the release of acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS, a stimulatory neurotransmitter, inhibiting stimulatory effects, preventing muscle contraction, and causing flaccid paralysis.
• Autism spectrum disorder Autism spectrum disorder Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by poor social skills, restricted interests/social interactions, and repetitive/stereotyped behaviors. The condition is termed a “spectrum” because of the wide variability in the severity of symptoms exhibited. Autism Spectrum Disorder: neurodevelopmental disorder marked by poor social skills, restricted interests and social interactions, and repetitive and stereotyped behaviors. This condition is termed a “spectrum” because of the wide variability in the severity of symptoms exhibited. Some individuals suffer from severe impairment in language and intellectual levels, while others may have normal or even advanced intellect Intellect Psychiatric Assessment. 
• Huntington disease Huntington disease Huntington disease (HD) is a progressive neurodegenerative disorder with an autosomal dominant mode of inheritance and poor prognosis. It is caused by cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (HTT). The most common clinical presentation in adulthood is a movement disorder known as chorea: abrupt, involuntary movements of the face, trunk, and limbs. Huntington Disease: progressive neurodegenerative disorder with an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance mode of inheritance. It is caused by CAG (cytosine-adenine-guanine) trinucleotide repeats in the huntingtin ( HTT HTT Huntington Disease) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, leading to neuron death and atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation of the caudate and putamen. A common clinical presentation in adulthood is a movement disorder known as chorea Chorea Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. Huntington Disease—abrupt, involuntary movements of the face, trunk, and limbs. Management is supportive.
• Schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia: serious chronic mental health disorder. Schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia is characterized by the presence of psychotic symptoms Psychotic symptoms Brief Psychotic Disorder, disorganized speech or behavior, flat affect, avolition Avolition Lack of initiative. Schizophrenia, anhedonia Anhedonia Inability to experience pleasure due to impairment or dysfunction of normal psychological and neurobiological mechanisms. It is a symptom of many psychotic disorders (e.g., depressive disorder, major; and schizophrenia). Schizophrenia, poor attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment, and alogia Alogia Poverty of speech. Schizophrenia. Management includes antipsychotics in conjunction with behavioral therapy.