Nerve tissue, synapses, and neurotransmitters

Nerve tissue consists of neurons, which are excitable cells that transmit information as electrical signals, and glial cells (e.g., oligodendrocytes, Schwann cells, astrocytes, microglial cells), which perform a variety of nonsignaling functions such as forming myelin to provide support and insulation between neurons, phagocytosing and removing cellular debris, removing excess neurotransmitters, and forming the blood-brain barrier. Oligodendrocytes myelinate neurons in the central nervous system (CNS), while Schwann cells myelinate neurons in the peripheral nervous system (PNS). Myelin sheaths increase the conduction velocity of signals across axons. Inflammation and loss of the myelin sheath are the underlying pathologic processes in multiple sclerosis (CNS) and Guillain barre syndrome (PNS). Neurons are composed of dendrites, cell bodies, axons, and axon terminals. Based on their conduction velocity, diameter, and myelination, nerve fibers (axons) are classified into large, myelinated fibers with fast conduction velocity (group A); small, myelinated fibers with slow conduction velocity (group B); and small, unmyelinated fibers with slow conduction velocity (group C). Neurons communicate through the transmission of action potentials across junctions between them called synapses. Synaptic transmission can be chemical or electrical. Chemical synaptic transmission is the transfer of signals through the release of neurotransmitters (e.g. acetylcholine, dopamine, norepinephrine) from presynaptic terminals to postsynaptic receptors. Electrical synaptic transmission is the transfer of electrical signals through gap junctions. Alterations in neurotransmitter levels have been observed in various neurological diseases, including Parkinson disease (decreased dopamine), schizophrenia (increased dopamine), depression (decreased dopamine, norepinephrine, and serotonin), and Alzheimer disease (decreased acetylcholine).

General

• Nerve tissue is the main tissue component of the nervous system and is primarily composed of neurons and supporting glial cells.
• The nervous system is divided into two main components:
  • Central nervous system (CNS): consists of the brain and spinal cord
  • Peripheral nervous system: consists of the nerves and ganglia outside the brain and spinal cord, including the cranial nerves, spinal nerves, and their roots, peripheral nerves, and neuromuscular junctions

Neurons

• Description
  • Polarized, signal-transmitting cells that comprise the central and peripheral nervous system
  • Classified into unipolar, pseudounipolar, bipolar, and multipolar depending on the number of protoplasmic processes (neurites)
  • Do not undergo mitosis
  • Composed of soma (cell body), axon and dendrites
  • Nissl staining positive in the cell body and dendrites, which have Nissl substance (aggregates of rough endoplasmic reticulum with bound polysomes)
• Parts
  • Soma: contains the cell organelles
    • Has Nissl substance
    • Pigments: melanin, lipofuscin
    • Cytoskeleton: microfilaments
  • Axon: the projection from a neuron's cell body along which action potentials travel to send intercellular signals
    • Connected to the cell body at the axon hillock; , which is a trigger zone for initiation of action potentials , and ends in a synapse
    • Lacks a regular rough endoplasmic reticulum and thus does not contain Nissl substance ^[1]
    • Cytoskeleton
      • Microtubules with associated motor proteins for rapid axonal transport
        • Kinesin: anterograde transport (– → +)
        • Dynein: retrograde transport (+ → –)
      • Neurofilaments
        • Provide structural support
        • Most abundant in axons and the proximal part of dendrites
        • Neurofilament protein is used as a marker for neuronal cells.
  • Dendrites
    • Branching, thin projections from the cell body of neurons that receive input from neighboring neurons and transmit it to the cell body
    • Contain spines that increase the number of synapses to other neurons
    • Have Nissl substance
    • Cytoskeleton: microfilaments

Supporting glial cells

Each myelinating SchwONE cell insulates only ONE axon.

Glial cells guard the axons of the nerve cells as COPS: CNS axons are myelinated by Oligodendrocytes; PNS axons are insulated by Schwann cells.

Myelin

• Insulating layer of modified plasma membrane that wraps around axons of nerve in a spiral structure
• Increases the space constant and the conduction velocity of signals traveling down axons
• Decreases membrane capacitance and increases membrane resistance
• Node of Ranvier
  • Unmyelinated regions between two adjacent myelinated segments of axons in the CNS and PNS
  • Contain a large amount of Na+ channels: allows saltatory conduction → increases the velocity of action potentials
• Demyelination: a process in which myelin sheaths of nerves become damaged, which impairs electrical conduction
  • Central demyelination occurs within the CNS (e.g., seen with multiple sclerosis, progressive multifocal leukoencephalopathy, leukodystrophies).
  • Peripheral demyelination affects the PNS (e.g., seen with Guillain-Barré syndrome).

Neuronal damage

• Responses to damage
  • Cellular swelling
  • Peripherally located nucleus
  • Spread of Nissl substance throughout the cytoplasm of the neuron (chromatolysis)
  • The distal injured part of the neuron undergoes Wallerian degeneration.

Layers of peripheral nerves

• Endoneurium
  • Thin inner layer of connective tissue around a single nerve fiber
  • Clinical significance: contains inflammatory infiltrate in Guillain-Barre syndrome
• Perineurium
  • Layer of connective tissue around nerve fascicles
  • Contains the blood-nerve barrier
  • Clinical significance: important layer in microsurgery during limb salvage surgical procedures
• Epineurium
  • Outer layer of dense connective tissue around a nerve
  • Contains nerve fascicles and blood vessels to the nerve

Nerve fibers are classified based on their conduction velocity, diameter, and axon characteristics.

C fibers have a slow conduction velocity due to their small diameter and lack of myelination.

Neurotransmitters

Neurotransmitters are endogenous substances that allow communication between neurons and, usually, induce a change in the target cell. There are two types of neurotransmitters:

• Conventional neurotransmitters: molecules that follow conventional synaptic transmission (see chemical synapse below)
  • Small molecule neurotransmitters: GABA, dopamine, norepinephrine, epinephrine, serotonin, histamine, ATP, glutamate, aspartate, adenosine, and acetylcholine
  • Neuropeptides: endorphins, enkephalins, substance P, and neuropeptide Y
• Unconventional neurotransmitters: molecules that are not stored in synaptic vesicles, may carry messages from the postsynaptic to the presynaptic neuron and can cross the cell membrane, acting directly on molecules inside the cells.
  • Endocannabinoids
  • Gasotransmitters: nitric oxide and carbon monoxide

Neurotransmitter receptors (neuroreceptors)

• Definition: a membrane receptor protein that is activated by a neurotransmitter
• Characteristics
  • Membrane-bound, activated by the binding of neurotransmitters
  • Found on presynaptic and postsynaptic neuronal membranes
  • Open or close ion channels, producing electrical signals
  • Excitatory and inhibitory responses are determined by the class of ion channel and by the concentration of permeant ions inside and outside the cell.
• Types of receptors
  • Ionotropic receptors (ligand-gated ion channels): form channels through which ions, e.g., Na⁺ and Ca²⁺, flow
  • Metabotropic ion receptors (G-protein coupled receptors): are coupled to intracellular G proteins that are activated upon binding to a ligand
  • Other: presynaptic receptors (autoreceptors)
    • Respond to the transmitter released by the same neuron
    • Regulate neurotransmitter release, synthesis, or impulse flow
    • Considered a homeostatic feedback mechanism

Ion channels ^[6]

• Definition: transmembrane proteins with a narrow pore that selectively permits particular ions to permeate the membrane
• Functions
  • Give rise to selective ion permeability changes
  • Detect the electrical potential across the membrane
  • Involved in changing of local transmembrane potentials
• Types of channels
  • Voltage-gated ion channels: selectively permeable to the major physiological ions (K⁺, Na⁺, Ca²⁺, Cl^-), responding to changes in membrane potential (e.g., depolarization, hyperpolarization); e.g., Na⁺ and Ca²⁺ channels
  • Ligand-gated ion channels: cell-surface ion channels that increase ion flux in response to ligand or drug binding to, e.g., G-protein-gated neurotransmitter receptors
  • Mechanically-gated ion channels: transmembrane ion channels that are activated by changes in the structure of the membrane and allow the passage of ions when open. Mechanically-gated ion channels are generally specific to one of the major physiological ions (K⁺, Na⁺, Ca²⁺, Cl^-).

Clinical significance of neurotransmitter changes

Definitions

• Synapses: the junction across which signals or action potentials are transmitted from a presynaptic to a postsynaptic structure (e.g., neurons, muscle).
• Synaptic transmission: the process of communication between two neurons, involving the release of a neurotransmitter by the presynaptic neuron and the neurotransmitter binding to receptors on the postsynaptic membrane
• Fast neurotransmission: direct activation of a ligand-gated ion channel by a neurotransmitter
• Neuromodulation: occurs when a neurotransmitter binds to a G-protein-bound receptor and activates a chemical signaling cascade

General

• There are two types of synapses: chemical and electrical
• Synapses can further be classified according to the structures between which they signal:
  • Axodendritic synapses: signal between axons and dendrites
  • Axoaxonic synapses: signal between axons
  • Axosomatic synapses: signal between axons and the cell body of neurons
  • Dendrodendritic synapses: signal between dendrites

Chemical synapses

A type of synapse that transmits signals between neurons separated by a cleft via a chemical neurotransmitter

Overview

• Composed of a presynaptic membrane, a synaptic cleft (the space between a presynaptic and postsynaptic neuron), and postsynaptic membrane
• Most neurotransmitters (e.g., GABA, glutamate, glycine) undergo the following steps: synthesis, storage, release, reuptake, and degradation

Mechanism (presynaptic and postsynaptic receptor interactions)

1. Neurotransmitter synthesis
   • Occurs in the presynaptic neuron
   • A precursor amino acid accumulates into the neuron.
   • The precursor is metabolized sequentially and yields a mature transmitter.
2. Neurotransmitter storage
   • Vesicles filled with neurotransmitters are stored in the presynaptic terminal and to be released in response to stimulation of the neuron
   • Synaptophysin is a major synaptic vesicle protein that is thought to play a role in synaptic vesicle formation and maintenance ^[8]
     • Expressed throughout the brain
     • Used as a marker for neuronal cells as well as neuroendocrine tumors
3. Neurotransmitter release
   • Action potentials in the presynaptic cell trigger the opening of voltage-gated Ca²⁺ channels in the presynaptic membrane, permitting Ca²⁺ influx.
   • Ca²⁺ binds to synaptotagmin (a protein anchored in the vesicle membrane), which initiates the vesicle docking to the presynaptic membrane and formation of SNARE complex. ^[9]
   • SNARE complex
     • Stands for Soluble NSF Attachment protein REceptor complex
     • Consists of several SNARE proteins, which are attached to either:
       • The vesicle membrane (v-SNARE proteins; e.g., synaptobrevin)
       • The presynaptic target membrane (t-SNARE proteins; e.g., syntaxin 1, SNAP 25 )
       • v-SNARE and t-SNARE proteins combine at the presynaptic membrane to form the SNARE complex.
   • During SNARE complex formation, the vesicle membrane and the presynaptic membrane merge, causing neurotransmitters to be released into the synaptic cleft.
4. Neurotransmitter binding and recognition by target receptors
   • Neurotransmitters act on receptors on the postsynaptic membrane, resulting in the influx of ions into the postsynaptic cell.
   • An action potential is created on the postsynaptic cell, completing the passage of the neurotransmitter from the presynaptic to the postsynaptic cell.
5. Termination of the action of the released transmitter
   • Neurotransmitter actions may be terminated by the following three interlinked processes.
     • Neurotransmitter reuptake: an active termination process triggered by specific transporter proteins on the presynaptic neuron or on glial cells where the neurotransmitter is stored
     • Neurotransmitter enzymatic degradation: a termination process triggered by enzymes in the synaptic cleft (e.g., acetylcholinesterase) yielding an inactive substance
     • Neurotransmitter diffusion: a dispersal of the neurotransmitter out of the synaptic cleft
6. Postsynaptic potentials (PSPs)
   • The postsynaptic response depends on the type of channel coupled to the receptor, and on the concentration of permeant ions inside and outside the cell.
   • Excitatory postsynaptic potential (EPSP)
     • A depolarizing potential that develops in a postsynaptic membrane as the result of increased influx of cations into the postsynaptic cell
     • The summation of multiple excitatory postsynaptic potentials can cause the postsynaptic neuron to reach the threshold for the generation of an action potential.
     • Examples include: neuromuscular junction, nicotinic synapses (e.g., autonomic ganglia), NMDA synapses (e.g., glutamate and aspartate neurotransmitters)
   • Inhibitory postsynaptic potential (IPSP) ^[10]
     • A temporary hyperpolarizing or depolarizing potential that develops in a postsynaptic membrane as the result of increased influx of anions into the postsynaptic cell.
     • Inhibitory postsynaptic potentials cause the postsynaptic neuron to move away from the threshold, decreasing firing and propagation of action potentials.
     • Examples include: GABAnergic synapses, glycine synapses (e.g., occur in the Renshaw cells of the spinal cord)

Certain proteolytic enzymes, e.g., tetanus toxin and botulinum toxin, can cleave SNARE proteins, thereby inhibiting neurotransmitter release into the synaptic cleft and, thus, causing spasms and paralysis.

Neuromuscular junction (NMJ)

• Definition: a type of chemical synapse that occurs between alpha motor neurons and skeletal muscle
• Motor unit: an alpha motor neuron together with the group of muscle fibers it innervates
• Presynaptic neuron: action potential → depolarization of the presynaptic membrane → opening of voltage-gated Ca²⁺ channels → influx of Ca²⁺ into the presynaptic terminal → SNARE complex-mediated fusion of vesicles with the presynaptic membrane → release of acetylcholine (ACh) from vesicles into the synaptic cleft
• Muscle fiber: binding of ACh to its receptor on the postsynaptic membrane of muscle (motor end plate) →: depolarization of the postsynaptic membrane → end-plate potential (EPP) → stimulation of voltage-sensitive dihydropyridine receptors (DHPR) → coupling with ryanodine receptors (RR) → release of Ca²⁺ from the sarcoplasmic reticulum (SR) → tropomyosin releases the myosin-binding site on actin → binding of myosin and actin → muscle contraction
• Synaptic cleft: acetylcholinesterase (AChE) breaks down ACh → acetate and choline → reuptake of choline into the presynaptic membrane → resynthesis of ACh

Electrical synapses

• A type of synapse that transmits signals between neurons joined by a gap junction by the flow of electrical current (i.e., movement of ions).
• Unlike chemical synapses, which require the transmission of a neurotransmitter across a cleft, electrical synapses transmit the signal directly and without delay.
• Found in the heart and smooth muscle
• Allows bidirectional flow of information between cells

• Definition: substances that enhance neuronal survival and differentiation
• Overview ^[6][11][12]
  • Neurons compete for survival-promoting agents during their development
  • NTFs ensure a match between the requirement for appropriate target innervation and the number of surviving neurons
  • Functions include regulation of nervous system development (e.g., cell proliferation, migration, differentiation, dendritic and axonal growth, synaptogenesis, synaptic plasticity), of regressive events (e.g., cell death or survival, axon and synapse elimination) after injury, and of synaptic competition and by modifying both synaptic transmission and structure