NERVE PHYSIOLOGY & SYNAPSE

Astrocytes

• CNS (in gray matter and BV)

  • REGULATE microenvironment of neurons: control ion balance (K+)

  • Support and nourish neurons

  • Form the BBB

  • Repair and scar formation after CNS injury

• They are the MAIN GLIAL CELLS CONTROLLING NEURONAL ENVIRONMENT IN THE CNS

• Macroglia that send processes that envelop synapses and the surface of nerve cells

Ependymal Cells

• Roles:

  • Produce and circulate cerebrospinal fluid (CSF) (with help of choroid plexus).

  • Barrier between CSF and CNS tissue; may help in selective transport.

  • Some ependymal cells have cilia that help move CSF.

• Key point: They DO NOT REGULATE the extracellular microenvironment of neurons; their role is mainly in CSF production and circulation.

Satellite cells

• Surround neuronal cell bodies in ganglia

• Microenvironment REGULATOR in PNS

  • Control ion balance (K+)

  • Provide structural support

  • Participate in modulating neuronal excitability

• PNS equivalent of astrocytes

Oligodendrcytes

• CNS (brain and spinal cord)

  • Form myelin sheath

  • Insulate axons to increase conduction velocity

• Support axons metabolically to some extent

  • they DO NOT REGULATE the extracellular environment like astrocytes

Trigger Zone

• Axon hillock + initial segment

• Part where the action potentials are initially generated

Axon

• It includes the myelinated segments and the nodes of Ranvier

• Transmitting portion

  • Myelinated

  • Unmyelinated

Myelinated axons

• AP “jumps” via saltatory conduction between nodes of Ranvier.

• Nerve fibers coated by an insulating myelin sheath

Unmyelinated Axons

• Nerve fibers that lack a myelin sheath

• Protective coating

• Smaller in diameter

• Conduct nerve impulses at a slower speed

Dendrites

• Mainly receive signals

• Where NT receptors are found

• Collects and stores all incoming information from axon terminals

• Conduct electrical impulses toward the cell body of the nerve cells

Soma

• “Cell body”

• Integrates signals

• May contribute to local potentials but not long distance conduction

• Where organelles, nucleus is seen

Velocity of Conduction

• How quickly a signal like an electrical impulse in a nerve or hear transfer, travels from one point to another

• Known as Nerve Conduction Velocity (NCV)

• Larger diameter = lower ressitance → faster conduction

Ion Channels

• Cell membrane integral proteins that permit passage of certain ions

  • Selective for specific ions

  • Maybe open or closd

• Selectively based on distribution of charges and size of channels

Voltage-Gated Channels

• Opened or closed by changes in membrane potential

  • Activation vs. Inactivation gate of nerve Na+ channel

Ligand-Gated Channels

• Opened or closed by hormones, 2nd messenger, NTs

  • Skeletal muscle AChR (Nm receptor) that opens gate for Na+ and K+ when Ach binds

Ligand

Known as “messengers”

Messenger

Can either be hormones or neurotransmitters

Diffusion Potential

Potential difference generated across a membrane because of concentration difference of an ion

Equilibrium Potential

• Nernst potential

• Exactly balances [opposes] the tendency for diffusion caused by concentration difference

• Perfectly balanced by the opposing electrical force, resulting in no net movement of that ion across the membrane

Resting Membrane Potential

• Exhibited by all cells

• Refers to intracellular charge

• Normal nerve: -70 mV

• Caused by:

  • Nernst Potential for Na+ and K+

  • K+ leak channels

  • Na+-K+-ATPase Pump

High Resting Conductance to K

Nerve membrane more permeable to K+ than Na+

Hyperpolarizing

Causes reduction of potassium leak out of the cell

Action Potential

• Exhibited only by excitable cells (neurons, all muscle types)

• Consists of rapid depolarization/upstroke “on” followed by repolarization “off”

Characteristics of a True Action Potential

1. Stereotypical size and shape

2. Propagating

3. All-or-none

Depolarization

• Make the MP more positive

• Opening of Na-activation gate (m gate) → Na-inward current

Repolarization

Closing of Na inactivation gate (h gate) → stop Na-inward current

Opening of K gates

K outward current

Hyperpolarization

Make MP more negative

Inward Current

Positive charges flow into the cell causing depolarization

Outward Current

Positive charges flow out of the cell causing hyperpolarization

Threshold

• MP where AP is inevitable

• net inward current > net outward current

  • Na+ inward current > K+ outward current from K leak channels

Overshoot

Occurs during an AP when MP > 0 mV

Undershoot

• After-hyperpolarization

• Occurs during an AP when MP < RMP

Absolute Refractory Period

• Occurs during AP when no new AP, can be elicited no matter larger the stimulus

  • Basis: closed Na+-inactivation gates

Relative Refractory Period

• Occurs during an AP after ARP when a new AP can be elicited by required greater than usual Na+ inward current

  • Basis: prolonged opening of K+ channels

Accommodating

• Occurs when cell membrane is depolarized but not rapidly enough, thus causing Na-inactivtion gates to eventually close → no AP

  • Hyperkalemia

Electrotonic Potential

• non-propagated local potential

  • Due to local change in ionic conductance

Generator potential

• Synaptic potential

• Local electrical charge in the generator/sensitive region of the receptor cell

  • Graded potential

Synaptic Potentials

• Principal inputs charge to which a neuron responds

• Conductance changes are triggered by neurotransmitters

Upstroke of the Nerve Action Potential

There is net inward current and the cell interior becomes less negative

Lidocaine

• Blocks neuronal voltage-gated sodium channels responsible for AP generation and propagation

• It can also act on cardiac muscles

  • Cause arrythmias

Conduction velocity

• Distance/Latent Period

• It is increased by:

1. Fiber size

2. Myelination

3. Nodes of Ranvier

Fiber Size

The larger the nerve fiber, the smaller the internal resistance, and the faster the conduction velocity

Nodes of Ranvier

• Unmyelinated portion of the axon

• 1st part where signal travels

• Regenerate AP

• Contains the highest concentration of Na+ channels per square micrometer of cell membrane

Rapid Na+ Channel Gating

Rapid gating allows for rapid action potential upstroke, which speeds conduction

Wide Axons

• Have lower resistance

  • Allowing electrical signals to travel farther without much amplification

Myelination

Myelin allows electrical insulation, reducing leak currents that short circuit the signal

Saltatory Conduction

AP jumps electronically from node to node reducing the need for slower active regeneration steps

Myelinating the nerve

The velocity of conduction of action potentials along a nerve will be increased by ______

Microglia

• A tissue macrophage that acts as:

  • Scavenger cells

  • Removing debris

  • Resulting from injury, infection, and disease

    • Multiple sclerosis, AIDS-related dementia, PD, Alzheimers

Schwann Cells

Helps in regeneration and remyelination in the PNS

Fibrous Astrocytes

Astrocytes in the white matter

Protoplasmic Astrocytes

• Astrocytes in gray matter

• With granular cytoplasm

• Maintain appropriate concentration of ions and NTs by taking up K+ and the NTs: GLUTAMATE AND GABA

Initial Segment

• “Axon Hillock”

• Where AP starts

Neural fibril

Branches of the axon

Terminal Boutons (End-Feet)

Distal tips of the axon

Voltage-Gated Calcium Channels

• Stimulated by AP; triggers release of NT into the synapse

• It is open when the action potential depolarizes the membrane of a terminal button

Lambert-Eaton Myasthenic Syndrome

• Autoimmune disease marked by autoantibodies against these voltage-gated calcium channels → prevents ACETYLCHOLINE from being released to the neuromuscular junction

Exocytosis

Mechanism for the release of neurotransmitters in the synapse

Excitatory

Depolarizes

Inhibitory

Hyperpolarizes

Multiple Sclerosis

• Autoimmune disease directed against the components of the myelin sheath

  • Brain MRI and CSF analysis (presence of oligoclonal bands)

Paraparesis

Weakness in lower extremities

Optic Neuritis

• Blurred vision

• change in color perception

• central scotoma

• pain in eye movement

Synaptic Transmission

• Orthodromic (Synapse to Axon) rather than Antidromic (Axon to Synapse)

One-to-one synapses

• One neuron, one post-synaptic element

  • Neuromuscular junctions or NMI

Many-to-one synapses

• Many neurons, one post-synaptic element

  • Spinal motor neurons

Excitatory Post-Synaptic Potentials

• Depolarizes postsynaptic cell, brings it closer to threshold

  • Due to Na+ influx

Inhibitory Post-Synaptic Potentials

• Hyperpolarizes post-synaptic cells

  • Due to Cl- influx

Spatial Summation

• It means several firings in different places

• Not strong enough to cause a neuron to fire

• If fire simultaneously, their combined effects will cause AP

Temporal Summation

• Means several firings at the same place, which won’t cause an AP if they have a pause in between.

• Several firings in rapid succession will cause neuron to each the threshold for excitation

Facilitation/Augmentation/Post-tetanic Stimulation

Brings cell closer to threshold

Endplate Potential

• In skeletal muscle motor endplate

• Increase in Na+ conductance (Na+ influx)

Fast Inhibitory Post-Synaptic Potential

• Opening of a chemically gated ion channel

  • most direct

• Rapid & of short duration

• Can be caused by opening of Cl- channels (Cl- influx)

• Opening of K+ channels (K+ efflux)

• Closure of Na+ or Ca2+ channels

Fast Excitatory Post-Synaptic Potential

• Increase in Na+ conductance (Na+ influx)

• Ca2+ conductance (Ca2+ influx)

Slow Excitatory Post-Synaptic Potential

• Decrease in K+ conductance (Slow K+ efflux)

Presynaptic Inhibition

Opening of voltage-gated K+ channels (K+ efflux)

Neurotransmitters

• Function: chemical messengers

• For communication between neurons

• Maybe excitatory or inhibitory

Monoamines

Ach, serotonin, histamine (ASH)

Catecholamines

Dopamine, NEpi, Epi (DEN)

Amino Acids

Glutamate, GABA, Glycine (G3)

Large molecule neurotransmitters

Neuropeptides including substance P, enkephalin, vasopressin, and a host of others

Acetylcholine

• Maybe excitatory or inhibitory

• Found in:

  • NMJ

  • Sympa and Para

  • Para and preganglionic neurons

  • Some Sympa postganglionic

  • Basal ganglia

  • Large pyramidal cells

  • Motor cortex

  • Gigantocellular neurons

• Created by: Choline Acetyltransferase (Acetyl coA and Choline)

• Degraded by: Acetylcholinesterase into Acetate and Choline (1/2 of which will undergo reuptake)

• Opens Na-K pump that depolarizes the muscle endplate to a value halfway between Na K equilibrium potentials

• Triggers REM sleep

• Decrease levels in:

  • Huntington dementia and Alzheimer dementia

Norepinephrine

• Found in the locus coeruleus of the pons

  • NeuroMODULATOR in the CNS

  • NeuroTRANSMITTER in the PNS

• Derived from tyrosine

• Synthesized INSIDE synaptic vesicles

• Half-life: 2 minutes

• Primary NT from postganglionic sympathetic neurons

  • For arousal/wakefulness

Epinephrine

• Secreted mainly by adrenal medulla

• Greater Beta-2 action than NE

• Relieve effects of bee sting by decreasing contraction of airway smooth muscles

  • Bronchodilator

Dopamine

• Secreted in substantia nigra “pars compacta” (fine-tunes movement)

• Generally excitatory

• Derived from tyrosine

• Inhibited by GABA when it is released

• Amphetamines: released is enhanced

• Also secreted by hypothalamus (Prolactin-Inhibiting Factor or PIF) to inhibit prolactin

  • D1 Receptor: activates adenylate cyclase using Gs protein

  • D2 Receptor: inhibits adenylate cyclase using G1 protein

• Low level: Parkinson’s

• High level: in D1 in Schizophrenia

• Schizophrenia: can be due to abnormalities in the prefrontal, frontal and limbic system (hippocampus)

Serotonin

• Found in the median raphe of the brainstem from tryptophan, converted to melatonin

  • Low level: depression

• Happy hormone

Nitric Oxide

• Short-acting inhibitory NT in GIT and CNS

• Macrophages release: helps kill bacteria

• No synthase converts Arginine to citrulline and NO

• Classification: Inhibitory, non-adrenergic, non-cholinergic

• Permeant gas, inhibitory NT, vasodilator

  • cGMP

  • penile erection

Parkinson’s Disease

Degeneration of dopaminergic neurons

Electrical Synapse

• Impulses can be regenerated without interruption in adjacent cells

• Functions in synctium

  • Ex: smooth and cardiac muscles, brain, and glial cells

• Are less common than chemical synapses

• Are important in:

  • Arousal from sleep

  • Mental attention

  • Emotions and memory

  • Ion and water homeostasis

Chemical Synapse

• Almost all synapses used for signal transmission in the CNS

  • First neuron secretes a chemical substance called neurotransmitter at the synapse to act on receptor on the next neuron to excite it, inhibit or modify its sensitivity

Synaptic Transmission

• Involves:

  • the release of NT from the presynaptic cell

  • diffusion of NT across synaptic cleft

  • binding of the NT to receptors on the postsynaptic cell

• It ends when NT dissociates from the receptor and is removed from synaptic cleft

Terminal buttons

An action potential travels down an axon to the _____ or known as synaptic knobs at the end

Snares

Found on both vesicle and nerve terminal membrane

V-Snares

• VAMP (vesicle associated membrane protein)

• Synaptobrevin

• tightly binds syntaxin and SNAP25

T-Snares

• syntaxin and SNAP25

Vesicle docking

It occurs when the V-SNAREs and T-SNAREs bind together

SNAP-25

Located on the T-SNARE, helps fuse the two SNAREs together forming a complex

Clathrin

• After neurotransmitter release, the vesicular membrane is coated with this protein

• Transferred to the endosome, where the membrane is reused for new vesicles and refilled with neurotransmitters

Receptors

NT binds to ________ in the postsynaptic membrane

2 Types of Receptors

1. Receptor that is part of an ion channel

2. Receptor coupled with a specific G protein and a second messenger system