Download the nervous sys. The function of neuron & Glia

The nervous system:
1. The Functions of Neurons and Glia
Anatomy & Physiology
Spring 2016
Stan Misler
<[email protected]>
Table of contents
• Introduction: what the nervous system is
composed of and what it does
• Structure of neurons
• Function of neurons: How neurons spread
electrical impulses by conduction and talk to one
another by synaptic transmission
• The Reflex arc
• Glial cells
• Introduction to neuron dysfunction caused by
toxins and genetic lesions
Neuron composed of
dendrites, cell body and axons
conduct electrical impulses Is
partially wrapped in glia cells
for insulation (like plastic
surrounding a copper wire)
The central nervous system
(Brain + spinal cord):
Weighs Weighs 3 lb with consistency
of soft jello; contains 100 billion neurons
in chains + helper glial cells and blood
vessels; cerebral cortex accounts for 80
% of mass; metabolically very active
getting 20% of body’s blood flow for 2%
of body mass
Schematic representation of the nervous system
Afferent fibers in bundles
carry impulses from
peripheral or internal
sensory receptor organs to
the CNS. Efferent fibers
carry impulses from CNS to
peripheral effector organs
(muscles of various types
and glands)
Enteric nervous system is in gut
Nervous system is basis for:
(a) sensation: vision, hearing, touch, smell, taste, pain
and heat receptors at periphery and internal receptors
sensing stretch and nutrients all projecting to the brain
(b) body movement ( + gait, station, balance): reflex or
fixed movement in response to stimuli of pain, touch or
stretch vs. voluntary movement formulated by brain
(c) modulation of involuntary (vegetative) functions:
changes in contraction of gut or heart muscle and
stimulation or inhibition of fluid and hormone secretion
by glands
(d) memory and learning: due to strengthening or
proliferation of synapses
(e) behavior: integration of complex movement
by sensory input or by activation of multisystem
intrinsic neural circuitry (fixed action pattern)
(f) Cognition : comprised of wakefulness;
selective attention; language use; memory /
forgetting; sensory perception; problem solving;
thinking / creativity; and decision making
Structure of neuron
Dendritic branches
(resembling branches of a
tree) carry small electrical
signals generated at periphery
of neuron to cell body.
In the cell body these signals
add. If the sum of these signals
is large enough it will trigger a
nerve impulse which can travel
down the axon and end in a
synaptic terminal or knob near
the next neuron in the chain. In
response to the nerve impulse
these knobs release chemicals
which can excite the next
neuron in the chain. The cell
body contains a nucleus and
all of the apparatus for protein
and membrane (lipid bilayer)
synthesis needed by the axon
and dendrites
Types of neuronal structure:
variation on pattern of input region (dendrites), integrative region (start
of axon where action potential is triggered), conductive region (axon)
and output or synaptic region (nerve terminal)
(i)
(ii)
(iii)
(iv)
All neurons are derived from common neuroepithelial cells of embryo
All neurons have morphological and functional asymmetry (dendrites vs. axon)
All neurons are made excitable by electrical and chemical stimuli
All neurons inherit same complement of genes but only express a restrictive set to
code for enzymes needed to make neurotransmitters, structural proteins to
determine structure of neurons, ion channels to give ride to action potentials of
different waveforms, receptors for different transmitters and other secretory products
How neurons generate their electrical signals
and transmit them down the axon
All cells separate concentrations of ions, especially Na and K, across
their cell membranes. The outside fluid, which bathes the cell, is rich
in Na (130 mM) but poor in K (5 mM), while the inside fluid, or
cytoplasm, of the cell is rich in K (130 mM) but poor in Na (10 mM).
These differences in ion concentrations are known as ion
concentration gradients.
The fact that membrane is permeable to K but barely permeable to
Na produces a voltage across the membrane called a resting
membrane potential ( = RMP). This is usually 1/14 of a volt inside
negative (or -70mV) and is measured by poking the cell with a glass
microelectrode filled with a high KCl solution.
Nerve cells are special because they are excitable. In response to a stimulus
(chemical, voltage pulse or stretch) which charges the membrane potential to a
threshold voltage of -50 mv, a nerve cell rapidly changes its membrane’s
relative permeabilities to Na and K (PNa and PK). The membrane becomes
very permeable to Na which can move down its concentration gradient into the
cell (high Na out to low Na in). This changes the amplitude and polarity of the
membrane potential (MP) from -70 mV to +20 or + 30mV (depolarization).
However, over 1 ms the membrane loses its permeability (P) to Na and
increases its permeability K resulting in the recovery of the membrane
potential back to the RMP or slightly negative to RMP. This spike of voltage
change (from -70 to +20 or +30 and back again to -70 mV) propagates as an
electrical wave (or spike impulse) called the membrane action potential (AP).
The AP travels down the neuron’s long cable-like axon at velocities up to 10s of
meters per seconds particularly when the axon is myelinated
PNa increases
PNa decreases &
PK increases
PK returns
to baseline
Ion Channel gating and excitability
Underlying the resting potential and AP are the opening
and closing of ionic channels = pores, of angstrom
diameter, which run through specialized multimeric
proteins spanning the plasma membrane, a lipid bilayer
(1) These channels are selectively permeable to one or
more ionic species (among these are K, Na, Ca, Cl). Ions
traverse channels down an electrochemical gradient
(2) Channels flicker open and closed spontaneously but are
gated to open/close in a more concerted fashion by (i)
external ligands or transmitters (including acetylcholine);
(ii) DVm; (iii) membrane stretch; or (iv) cytoplasmic
messengers (including Ca, cGMP) Each channel opening
gives rise to a flow of thousands of ions per millisecond
making the channel opening detectable as a step jump of
current
(3) Over time channel activity is modulated by
phosphorylation at specific internal sites and/or by
insertion into/retrieval from the plasma membrane.
(4) Channels identified by their ionic selectivity, gating and
pharmacology (drugs that open or close them)
Details of voltage gating of ion channels
The model of gating of a channel in the AP is that
on changing MP from -70 mV inside to -40 mV
inside there is movement of charged voltage
sensor wings of the channel within the
membrane thereby opening the criss-crossed tail
of channel and allowing ions into the vestibule of
the channel where ions are stripped of water. If
the ion is of the right size and charge it can move
through a selectivity filter and out of the channel
(top two cartoons)
In some types of channels this followed by
slower movement of ball-on-chain into channel
to occlude pore from its cytoplasmic side.
However on return to -70 mV inside the ball on
chain is swept out of the channel before the
channel pore closes. The channel is then ready to
reopen when the membrane voltage is returned
to -40 mV (bottom cartoon)
Ion Pumps, channel inactivation; refractory period
between spikes; one way saltatory conduction of AP
1. After a train of APs the nerve has gained some Na and lost some K. To make
sure the ion concentrations recover to their original quantities, a Na/K pump
within the membrane moves Na out and K in. Because the pump is moving ions
against their concentration gradients requires energy (breakdown of stored ATP.
2. Recall that after Na channels have been activated and open a few times they
close down and are not available to open until they have sat at the RMP for at
least several milliseconds (channel inactivation). Inactivation lengthens the
smallest interval between spikes (refractory period) and the maximum frequency
with which the axon can conduct APs (at most a few hundred per second). At any
higher frequency the AP is aborted and does not propagate (all or none feature).
Na channel inactivation also makes conduction possible only in one direction,
that is from a region that has just been excited to a neighboring region closer to
the nerve terminal that has been at its RMP for several ms.
3. In a myelinated axon the ion channels are clustered at the nodes of Ranvier,
The impulse jumps from one node to the next one down the line without losing
its shape. This is called saltatory conduction
Summary of features of AP
1. Initiation threshold
2. Refractory period
3. All or none
4. Conduction without decrement if axon
is myelinated
The synapse
Neurons contact each other or muscle cells at synapses. These are
closely apposed areas of chemical transmitter release, from knoblike ending of a presynaptic neuron, and transmitter reception by
the dendrite of next neuron in the chain or by a muscle
membrane. The knob-like ending of the pre-synaptic cell contains
small 40 nm diameter vesicles filled with neurotransmitter and
large mitochondria to provide it with local ATP. The post-synaptic
membrane is filled with neurotransmitter receptor channels. The
two membranes are separated by a 150 nm gap across which the
released transmitter must diffuse.
Chemical Neurotransmission at simplest synapse
(between motor nerve terminal and skeletal muscle) :
Depolarization-secretion coupling at presynaptic terminal (Ca entry
during AP -> transmitter release) and reception-depolarization coupling
at post-synaptic muscle cell (opening of acetylcholine receptor channel
allowing Na entry -> post-synaptic potential
Opening of Voltage activated Ca
channels near vesicle attachment
sites raises local [Ca]; vesicles
containing thousands of transmitter
molecules fuse with plasma
membrane and release their
contents, here acetylcholine (Ach),
into synaptic cleft by a process
known as expcytosis
Ach binds to Ach receptor channels
(combination of ach receptor and
cation selective channel -> Na entry
into muscle cell giving rise to postsynaptic (or endplate) potential. If 50
vesicles fuse within 1 ms after the
presynaptic AP the amount of Ach
released brings MP to threshold for
activating an AP in the muscle cell
Details of synaptic transmission
(i) Voltage activated Ca channels, which contribute to the nerve terminal AP, are located
very near vesicle attachment sites so entry of several thousand Ca molecules over 1 ms can
raise the local effective internal [Ca] from 100 nM to 10s of uM and trigger the fusion of
the vesicle with the presynaptic membrane (exocytosis)
(ii) Each 40 um diameter vesicle stores and synchronously releases a packet of many
thousands of acetylcholine molecules. Each packet produces ~0.5 mV change in RMP in the
positive direction. At least 50 quanta must be released over 1 ms by Ca entry during the
nerve terminal AP to produce a post-synaptic or endplate potential (epp) of 25 mV from
rest. This change in MP is enough to bring the muscle membrane to threshold for firing
trigger its own AP. This rate of “evoked” quantal release is > 1000 fold higher than
spontaneous (or resting) rate of exocytosis (at most 1 vesicle /s).
(iii) After exocytotic release of transmitter the fused vesicle membrane gets coated by
clathrin and is then retrieved from the nerve terminal membrane by a process known as
endocytosis. The retrieved vesicle fills with transmitter and is attracted to the nerve
terminal membrane where the intertwinement of vesicle SNAREs with plasma membrane
SNARES pulls the vesicle close to the plasma membrane and primes it for for another bout
of exocytosis.
(iv) Even small nerve terminal contains hundreds of vesicles in different states of readiness
for release including those moving in the cytoplasm and those tethered or hooked onto the
presynaptic membrane by SNAREs
(v) A Ca pump rids the presynaptic terminal of excess cytosolic Ca to insure that vesicles do
not clump together or fire off randomly
The central miracle of exocytosis: how granules get to, dock at,
get “primed” and then fuse with the plasma membrane (an
“exocyst complex”) for fusion pore formation
Diffusion of vesicles from microtubule to
membrane; vesicles then become ensnared to
plasma membrane by intertwinement of vesicle and
plasma membrane SNARE proteins
Protein components of vesicle membrane
a. Attachment devices for vesicle transport
b. Vesicle or v-SNAREs to intertwine with plasma
membrane target or T-SNARES (docking and
priming
c. Ca sensors (synaptotagmins)
Ach response and vesicle and Ach
metabolism at skeletal NMJ
(i) Acetylcholine binding to transmitter
receptors sites within channel (top left) ->
conformational change of receptor complex
and opening of constriction in pore (top right)
(ii) Rapid disposal of released Ach in the synaptic
cleft: diffusion of Ach out of cleft to be disposed of
by glia and degraded to choline + acetylCoA by
acetyl cholinesterase in synaptic cleft (bottom lft.
Free choline is taken back up into the presynaptic
terminal by plasma membrane. These reactions
limit the active time of Ach in synaptic cleft to
several millisec. If this were not so the channel
bound to Ach would go into a desensitized state and
be unavailable to open for many seconds (bottom
left)
•(iv) Retrieval and Recycling of vesicle membrane
fused with pre-synaptic membrane (ATP
dependent). Capture of vesicle membrane
(endocytosis) for recycling: kiss and run vs. more
complete kiss and stay fusion into membrane the latter
with endoctyosis consisting of complex recycling of
clathrin -coated membrane recovery (bottom right)
Membrane
recycling
Transmitter synthesis and degradation
What are the major energy (ATP)
requiring processes of the brain?
Stringing together neurons: the reflex arc
How MDs Check Simple Spinal Reflex the Knee Jerk Response
a
1A
Reflex arc = stretch of muscle -> activation of
stretch receptor fibers in muscle -> activation
of 1A afferent nerve to spinal cord -> synaptic
transmission (release and reception of
glutamate) -> activation of a motor neuron to
muscle -> release of Ach at neuromuscular
junction -> muscle contraction to restore length
Glia (50 times number of neurons) and their
accessory, homeostatic function
Oligodendrocytes = myelination of axon
by wrapping -> 50 fold increase in
conduction velocity of AP
Radial glia cells = scaffold for neuronal
migration and axonal outgrowth
Astrocytes = Uptake and metabolism of
released neurotransmitters +
buffering of ions in extracellular
environment (take up of excess K) +
source of blood brain barrier
(encasement of capillary by end-feet of
astrocytes produces selectively permeable
to barrier to substrates
Microglia = Scavengers to remove debris
produced by dying neurons
oligodendrocyte
radial glia
astrocyte
microglia
Defects in neuron function
1. Toxins affecting peripheral nerve
Tetrodotoxin (TTX) from ovaries of
puffer fish fits in and blocks pore of
voltage activated Na channels at
nodes of Ranvier and blocks AP
conduction -> paralysis of diaphragm
and block of lung ventilation
aLatrotoxin (aLTx) from venom
glands of black widow spider makes
Ca permeable channels in
presynaptic terminal -> massive
quantal release (left)-> depletion of
vesicle pool (right, A -> B) from
phrenic nerve terminal -> paralysis
of diaphragm -> KO breathing
2. Genetic Diseases of Nerves: Autoimmune
Multiple sclerosis = patch demyelination of
central neurons -> slowed conduction velocity or
even block of propagation of AP. Two or more
sporatic often resolving defects separated in time
and neural location including numbness and tingling,
monocular visual loss (optic neuritis), reduced
balance and uncoordinated gait, and slurred speech.
Warmth worsen symptoms as it desynchronizes AP
volleys in trunks of neurons.
Inflammation around small veins -> leakiness to
immune T cells and production of antibodies to
oligodendrocytes -> stripping myelin off the axon.
Inflammation may recede with time -> partial
remyelination or else formation of scar by astrocytes
Normal
MS
Myasthenia gravis =
antibodies and immune cells
targeting acetylcholine
receptor channels of muscle
endplate -> reduced number
of functional Ach receptor
channels and insufficient
depolarization of muscle to
give consistent muscle AP in
response to firing of motor
neuron -> muscle weakness
(especially drooping eyelids).
Weakness is treated with a
cholinesterase inhibitor
Enrichment topics
The Stereotypic Neuron: Anatomy and Physiology
(1) Dendritic tree = Sensory pole for signal detection:
Reception of transmitter inputs from other neurons at
spines -> post-synaptic potential (psp = a & b) while
sensory transduction of light or membrane vibration
(stretch) -> generator potential (GP = c)
(2) & (2a) Soma (cell body) & initial segment of
axon = sites of integration and conversion where the
amplitude and duration of small psps are summed
and encoded as trains of action potentials (APs)
(3) Axon = impulse propagator cable for APs. Axons
are often wrapped in a myelin sheath made of glial
membrane for insulation with interval electrical
boosting along length at nodes (*) to maintain fidelity
(4) Presynaptic terminal = secretory pole:
depolarization-dependent release of neurotransmitter
from synaptic vesicles by exocytosis (or pore formation
between vesicle and plasma membranes), onto sensory
pole of follower cell.
Overview of biochemistry of neuron
11
2
(1) (1) Dendritic tree: local organization of receptor
apparatus; Microfilament (actin)-based scaffold to
maintain shape and growth.
(2) Soma + initial segment of axon: Protein synthesis
beginning with DNA transcription to nuclear
transcriptional RNA and then to messenger RNA ->
translation on free ribosomes or rough endoplasmic
reticulum
Synthesis of organelles (vesicles and mitochondria
and microfilaments for transport along dendrites and
axons)
microfilament
(3) Axon: transport of organelles to and from
presynaptic terminals along microtubules by stepping
motors on surface of organelles
3
4
(4) Presynaptic terminal: (a) release of amino
acid or peptide derived transmitters and
reuptake and degradation amino acid-derived
transmitters (e.g., glutamate, acetylcholine) and
(b) endocytic uptake vesicle membrane
More precise Definitions and origins of key
electrical signals in neurons
(1) Baseline voltage or resting membrane potential, is roughly stable, inside negative
transmembrane voltage, Vm, ~-70 mV (A) largely due to high permeability to K and
operation of the Na/K pump to maintain ionic gradients
(2) Non-propagating analog impulse = postsynaptic potential (psp) or generator
potential (GP) = local, slow onset signal corresponding to the passage of inward
ionic current bringing Vm closer to 0 mV (depolarization, B) or the passage of
outward ionic current, bringing more negative to Vm,rest (hyperpolarization, C).
These signals sum with each other but all decrement with distance from sites of
initiation.
(3) Propagating digital impulse = action potential (AP) = rapidly depolarizing signal
brings Vm to (or positive to) 0 mV (the overshoot) and then rapidly returns it to
Vm,rest. (see D). Set off by sum of psps and GP that results depolarization
exceeding an all-or-none threshold.
Neuronal signals and their ionic origins
Action potential
Generator or post-synaptic potential:
Depolarizing
Equation for how Na entry depolarizes cell and K exit
repolarizes cell given on last slide below. This will be
presented in more detail in IB Physics Electricity Unit
Hyperpolarizing
Key evidence for Ca, quantal and vesicle hypotheses
Epp varies by defined steps from AP to AP
suggesting packet-like release of
transmitter
(upper) Electron microscopic view of of presynaptic ending containing thousands of
vesicles
(Lower) Effect of Spritz of 10K molecules of
Ach on endplate -> 0.5 mV depolarization =
effect of single packet or “quantum” of
release
Evidence that aLT makes Ca conducting channels
(bottom) that promote Ca entry into cytoplasm
(middle) and support fusion of synaptic vesicles with
plasma membrane (exocytosis) measured as increase
in nerve terminal surface (membrane capacitance Cm)
2. Specific loci for synaptic modulation
a.
b.
c.
d.
e.
f.
Changes in pre-synaptic Ca entry:
# Ca channels opening
Change in available (release –
ready) pool of vesicles = delivery
towards membrane; docking;
priming; refilling at high release
rates;
Change in size of quantum: either
pre-synaptic kinetics of fusion pore;
or blockade of post-synaptic
receptor channels
Changes in density of post-synaptic
receptor channels
Change in time that transmitter
remains in synaptic cleft before it is
broken down or taken up by pressynaptic cells
Modification of structure or
sprouting of new terminals (pre) or
dendrites (post)
3. Cell surface receptors, second messengers,
and the post-synaptic reception of transmitters
Direct response: ion channel is
transmitter receptor -> nearly
instantaneous response
Indirect response: transmitter receptor
coupled at a distance to ion channel via
G-protein cascade; response after 100s
of msec delay
Details of Ach response (nicotinic, nAch) at
skeletal NMJ
(ii) Acetylcholine binding to transmitter
receptors sites within channel ->
conformational change of receptor complex
and opening of constriction near pore
Ripped off piece of post-synaptic
response as well to ACH as patch
of membrane attached to cell
4. Modes of Synaptic Plasticity or Remodeling to change
synaptic efficiency constitute bases for memory:
“neurons that fire together wire together”
Homosynaptic potentiation:
increased frequency of synaptic
transmission -> post-synaptic
remodeling (increased number
of high current carrying postsynaptic receptors and “awakens
a quiet or silent dendrite”
Heterosynaptic potentiation :
high frequency stimulation of a nerve
synapsing onto the test presynaptic
terminal -> pre-synaptic remodeling
(increases number of active zones (regions
of coupling of Ca channels and vesicle\
release zones) and nerve terminal extension
and sprouting
Brain programmed to
pay special attention to
acquisition of novel
information. Also the
more you learn the
easier it is to learn
Nature vs. nurture: Dialogue between
genes and synapses
Putting synaptic inhibition into the picture
= synaptic potential produced by the interneuron excited by sensory afferent opens
chloride channels and brings MP of flexor motor neuron to RMP thus transiently
abolishing any AP activity that may be occurring in flexor motor neuron and relaxing
flexor muscle
Spinal cord
Quadriceps femoris
Hamstrings
inhibitory
Central excitatory transmitter = glutamate;
Central inhibitory transmitter = GABA