Download Membrane potential moves toward the K equilibrium

NEUROSCIENCE 1 – 07/01/2005 (page 1 of 2)
The Nervous System
Disorders
Look for asymmetry – good indicator that something is wrong
Common neurological disorders arise from non-neurological events (eg CVA)
The cause of “intrinsic” disorders is not known.
Disorders arise from either:
(a) neuronal degeneration
(b) neuronal dysfunction
Disorders can show either:
and/or
(a) loss of function
(b) abnormal function
Psychiatric disorders involve altered behaviour when no pathological cause can be
found.
Neurology and Psychiatry may overlap considerably.
Major Causes
(a) Trauma
>>eg skull fracture, spinal injury
(b) Cerebrovascular Accident (CVA)
>>eg stroke - blocked/bleeding artery
(c) Infection
eg meningitis **
(d) Neoplasia (tumour)
eg glioma: gen. of new tissue–little cranial space
(e) Metabolic disorders
eg diabetic neuropathy ^^
(f) Genetic disorders
eg Down’s syndrome.
(g) Environmental factors
eg heavy metal encephalopathy toxins (pb).
(h) Immunological factors
eg multiple sclerosis.
>>(a) and (b) most common
** infection via meninges (membranes covering brain) viral – non fatal, bacterial – fatal
huge influx of WBC and inflammation.
^^ degeneration of the peripheral nerves.
Epilepsy:
Abnormal Synchronous firing of neurones (EEG).
Parkinsons Disease: Loss of dopaminergic (specific group of) receptors in midbrain.
Bell’s Palsy:
Denervation of facial muscles (Left supplies Left, Right supplies
Right). Re-enervation is possible if infection treated.
Divisions
Division
Consisting of
Function
Central
Nervous
System (CNS)
Brain &
Spinal Cord
“Housekeeping” functions processing sensory
and motor information and maintaining internal
environment. Also supports higher functions of
percpetion, cognition, emotion and personality
CRANIAL NERVES CONNECTED DIRECTLY
TO BRAIN i.e. not via spinal cord
Peripheral
Nervous
System (PNS)
Peripheral
Nerves &
Ganglia
Provides sensory and motor innervation to the
body
Autonomic
Nervous
System (ANS)
Parts of CNS
& PNS
Controls visceral (organ) function and
homeostasis
Each division has local control of function, but some larger systems have several
communicating structures that are apart from one another eg the motor system
The cerebral hemispheres of the brain have contralateral control of the body (ie left
hemisphere controls right side of body. Thus there is lateralisation and localisation of
the NS.
Some higher functions only exist in one hemisphere - unilateral (eg language in left
hemisphere only).
PNS – cutting of an axon leads to sprouting from the cut end in order to re-establish a
connection – i.e. it can regenerate, although this is not always successful as the
connections can get mixed up with those of other neurons.
CNS – No axon regeneration is possible. This is most probably due to the
environment that the cell is in.
Neurons
Neurons are the functional cell units of the nervous system. The generate and
conduct electrical impulses releasing chemicals at synpases. They are supported by
neuroglia which outnumber neurons by 9:1
Synpase
Cell Body
Axon
Impulse Direction
Axons of neurones of the PNS can regenerate after injury although recovery may be
compromised by non-specific target innervation
Axons of the CNS do not regenerate
Diagnostic
Techniques
(a) History Taking
(i) Presenting complaint
(ii) Other illnesses
(iii) Social situation
(iv) Patient observation.
(b) Neurological Exam
(i) Level of consciousness
(ii) Speech
(iii) Mental State & Cognitive Function
(iv) Cranial nerve function #
(v) Motor function
(vi) Sensory function
# critical gives idea of brain function
(c) Neurophysiology
/Electrophysiology
(i) Electroencephalography (EEG)
(ii) Electromyography (EMG) & Nerve Conduction Study
(d) Imaging
(i) Computerised Tomography (CT) – hard tissues
(ii) Magnetic Resonance Imaging (MRI) – soft tissues ^^
(iii) Angiography of cerebral vasculature
^^ Consider: Size of pt. does it fit? + Metal implants? e.g. pacemaker.
Psychiatric Disorders
– Alter behaviour or mood
– No demonstrable pathology
– Neurology and Psychology may overlap considerably
NEUROSCIENCE 2 (page 1 of 2)
Cells of the Nervous System
Neuronal
Structure
All neurons are essentially the same in structure. The diversity of types of neuron
arises from the difference in the number and shape of their processes
(a) Cell body (Soma)
(i) Metabolic centre of the cell
(ii) Large nucleus
(iii) Abundant rough endoplasmic reticulum
(iv) Well developed Golgi apparatus(Hi levels of trafficking)
(v) Numerous mitochondria
(vi) Numerous lysosomes
(vii) Highly organised metabolically active cell
(b) Dendrites
(i) Receives incoming information
(ii) Branch away from cell body
(iii) Greatly increase surface area of neuron
(iv) Dendritic spines receive majority of synapses
(c) Axon
(i) Conducts impulse away from cell body
(ii) Emerges as the Axon Hillock
(iii) Myelinated or unmyelinated
(iv) Nodes of Ranvier
(d) Terminals
(i) Close to target the axon forms terminal branches
(ii) Specialised structures called synpatic terminals
(iii) Boutons (end of terminal) or varicosities along terminal
SEE Mosby Crash Course p11
INTRACELLULAR TRANSPORT – functional polarization
1. Anterograde transport.
- transport of materials needed for neurotransmission and survival away from cell body.
a)
fast anterograde - synaptic vesicles, transmitters, mitochondria
400mm/day
uses microtubular network and requires oxidative metabolism.
uses specific molecular motors.
b) slow anterograde
- bulk cytoplasmic flow of soluble constituents
-
2. Retrograde transport.
a)
-
fast retrograde – return of organelles.
transport of substances from extracellular space.
trophic growth factors, neurotropic viruses.
uses different molecular motors.
Neuronal
Sub-Types
Morphological Sub-Types
(a) Pseudounipolar neuron
Two fused processes which are both axonal
DRG neurones give rise to no dendrites and
receive no synapses.
(b) Bipolar neuron
Two axonal processes arising from the cell body
(c) Golgi Type I Multipolar neuron Cells that extend long distances
Pyramidal cells of Cerebral Cortex (purkinje)
(d) Golgi Type II Multipolar neuron Cells that have relatively short axons
Functional Sub-Types
(a) Sensory neuron
Conducts impulses from sensory receptors to the spinal
cord and brain. Usually pseudounipolar with one process
dividing into twowith one travelling to the CNS and one to a
sensory receptor.
(b) Motor neuron
(c) Interneuron
Conduct impulses from the brain and spinal cord to
effectors such as muscles or glands. Usually multipolar
with large cell body.
Responsible for the modification, coordination, integration,
facilitation and inhibition between sensory input and motor
output. The cell bodies and processes remain within the
CNS. Can be large multipolar or small local bipolar.
Neuronal
Organisation
Neurons of the CNS are grouped according to their function
(a) Nucleus
Unencapsulated cell bodies within CNS (func.similar) eg Brain Stem
(b) Laminae
Layers of similar neurons eg Cerbral Cortex, Cerebellum
(c) Ganglion
Groups of cell bodies in the PNS eg Dorsal Root Ganglia
(d) Fibre Tracts Bundles of axons in the CNS eg Corpus Callosum (white matter)
(e) Nerves
Bundles of axons outside CNS. Often mixed sensory/motor.
Synaptic
Organisation
Terminal portions of axons form synapses with other neurons which release chemical
transmitters to relay the impulse. Neurons receive multiple inputs which are integrated
at the postsynaptic neuron. The types of synapse are:
(a) Axodendritic (usually excitory effect)
(b) Axosomatic (usually inhibitory effect)
(c) Axo-axonic (either to the hillock or terminal and usually modulatory)
Neuroglia
Support cells of the CNS which perform varying functions. They are in close contact
with neurons and are essential for correct functioning.
1 ) Astroglia
(Astrocytes)
Astroglia are the most numerous of the neuroglia in the CNS and are closely
associated with blood vessels, ventricles, neuronal soma, synapses and nodes of
Ranvier
Functions:
2) Oligodendroglia
Myelinating cells of the CNS which are found in rows in axon tracts. They
have small spherical nuclei with few processes.
Functions:
3) Microglia
(a) Scaffold for other cell types
(b) Forms blood-brain barrier and brain-CSF barrier
(c) K+ buffering
(d) Removal and degradation of neurotransmitters (GABA)
(e) Divides in response to injury (scar tissue formation)
(a) Elaboration and maintenance of neuronal myelin
(b) Forms up to 40 myelin nodes for up to 50 neurons
(c) Very susceptible to nutritional state, toxins and infections
(d) Involved in myelin disease states (eg multiple sclerosis)
Derived from blood monocytes which invade to CNS during fetal development.
Relatively small cells with highly branched processes. They turn into large
phagocytosing cells during tissue damage.
Functions:
4) Other Glial Cells
(a) Resident macrophages of the CNS
(b) Antigen Presenting capability
(c) Role in tissue modelling
Ependymal Cells:
Form the simple cuboidal lining of the ventricles and
central canal of the cord. They are ciliated at the luminal surface and have
gap junctions NO TIGHT JUNCTIONS.
Schwann Cells
Envelop the axons of motor and sensory neurons. Produce myelin
for cells of the PNS. They also have the same functions as the
astrocytes and promote repair.
Satellite Cells
Perform the functions of astrocytes in the grey matter of the CNS.
NEUROSCIENCE 3 (page 1 of 3)
The Resting Potential
Diffusion – movement of molecules from one location to another solely as a result of their random
thermal motion
Diffusion – movement of molecules from a region of higher concentration to a region of lower
concentration
Diffusion equilibrium – uniform concentration and no further net movement
Flux – number of molecules (mols) crossing a surface per unit time (mols / s)
Electrical concepts
Electrical forces: another way to move molecules
Opposite charges attract and like charges repel
Force increases with the quantity of charge
Membrane Potentials: key concepts >>>>> Ions, not electrons

Potential (emf – electro-motive force): electrical force between ions that repels like
charges and attracts opposite charges. Units: mV

Current: movement of ions due to the influence of potential. Units: Amps

Resistance of a material: a measure of how hard it is for current to flow through it. Units:
Ohms
Lipids:
High Resistance, low permeability to ions
Salt solution (ICF and ECF):
Low Resistance, easy for ions to move
Resting membrane potential - e.m.f. (voltage) between the inside and outside of a cell:
•The zero reference point is outside the cell.
•The inside of the cell is negative compared to the ref.
•All cells have a membrane potential
•In excitable cells (neurons and muscle cells) it is particularly important to cell function
Understanding the ionic basis of the resting membrane potential
Membrane separates charge. This can happen because both:
1. The membrane is selectively permeable. Lets some ions through, but not others.
2. The concentration of at least one permeant ion is different on the two sides of the
membrane
Permeability of a membrane to an ion: number indicating how easy it is for the ion to cross the
membrane. Different for each cell !!!
>>
It is the flux of the ion through the membrane per unit of concentration gradient.
>>
Permeability depends on the type and number of specific ion channels in the membrane.
Generation of a membrane potential due to diffusion through a selectively permeable membrane:
Case 1. Membrane impermeable to all ions. No separation of charge.
Membrane potential = 0 V
Cell 1
NaCL @
0.15 mM
Cell 2
KCl @
0.15 mM
Case 2. Membrane permeable to K+ only (through K+ selective channels) . K+ diffuses down its conc gradient.
Compartment 1 gains + and compartment 2 loses + causing separation of charge across the membrane.
Cell 1
NaCL @
0.15 mM
More K+ diffuses and the voltage across the membrane increases (= membrane potential).
As + charge increases in compartment 1, it increasingly repels entry of K + .
Finally fluxes are equal, no net diffusion.
Flux of K+ down its conc gradient (from 2 to 1) is equal to the flux of K+ down the electrical gradient (from 1to 2).
Note that K+ conc in compartment 1 is still LESS than in compartment 2.
Only a miniscule number of ions cross; the change in concentration is very, very small
Cell 2
KCl @
0.15 mM
Case 3. Membrane permeable to Na+ only (through Na+ selective channels) . Na+ diffuses down its conc gradient.
Compartment 2 gains + and compartment loses + causing separation of charge across the membrane.
Note: the direction of charge movement is different than in previous case for a membrane permeable to K +
Cell 1
NaCL @
0.15 mM
Cell 2
KCl @
0.15 mM
Finally fluxes are equal, no net diffusion.
Note: compared to the previous case for a membrane permeable to K +
the sign of the membrane potential is opposite to previous case even though the conc’s are the same as in the
previous case
The key difference is the selectivity of the membrane
Electrochemical equilibrium for an ion is reached when its concentration gradient is balanced by the
electrical gradient across the membrane.
It is the electrical potential (voltage across the membrane) that prevents diffusion down the ion’s
concentration gradient.
Composition of the Main Fluid Compartments
_______________________________________________
in plasma*** in muscle
(mmol/l)
(mmol/l)
______________________________________________
Na+
150
10
K+
5
150
2+
Ca
2
10-4
* Na and Cl most abundant in PLASMA.
ClOrganic phosphates1Protein17-
110
5
1
5
130
2
* K and Organo-P most abundant in MUSCLE.
pH
7.4
7.1
---------------------------------------------------------------------osmolarity
285 mosm/l 285 mosmol/l
Na+ and K+ are most important ions for the resting potential of neurons
Nernst Equation: relates the size of the equilibrium potential of an ion to the size of its concentration
gradient
EX+ = (RT/ZF) ln (Co /Ci)
R = gas constant, T = Temp. o Kelvin, Z = charge on ion (-1 for Cl-, +2 for Ca+2), F =
Faraday’s number, 96,500 coulombs of charge per mol of ion with single charge, and ln
means log to base e
Substituting the constants and body temperature, and converting from ln to log gives:
EX+ = (61/Z) log10 (Co /Ci)
Nernst Equation: relates the size of the equilibrium potential of an ion to the size of its concentration
gradient
EX+ = 61 log10 (Co /Ci)
>>>
>>>
The equilibrium potential for Na using the concentrations above is +72 mV
The equilibrium potential for K using the concentrations above is – 90 mV.
To check sign of equilibrium potential: What sign does the inside need to keep the
concentration gradient as is?
Real membrane potential for typical neuron is –70 mV.
Not equal to the equilibrium potential of Na+, +72 mV
Not equal the equilibrium potential of K+, -90 mV
Real membrane potential is –70 mV, closer to K+ equilibrium potential because membrane is more
permeable to K+ than to Na+.
K+ diffuses down its conc gradient through permanently open K+ channels, so inside becomes
negative.
However, the membrane is slightly permeable to Na+, so some Na+ diffuses in down its conc gradient
and cancel out the effect of an equivalent number of K + diffusing out.
K+, Na+ and Cl- all contribute to the real membrane potential.
The size of each ions contribution is proportional to how permeable the membrane is to the ion.
Goldman Equation describes the resting membrane potential.
Vm = (RT/F) x [ ln PK (Ko) + P Na (Nao) + PCl (Cl-i) ] / [ PK (Ki) + P Na (Nai) + PCl (Cl-o) ]
Changes in membrane potential. Two types: Graded potentials and Action potentials
Changes in membrane potential: some definitions
Depolarisation
(from -70 to 0 mV).
Overshoot
(from 0 to +60 mV).
Repolarization
(from 0/+60 to -70 mV).
Hyperpolarization
(from -70 to -90 mV).
Resting potential
(-70mV).
Graded potentials: change in membrane potential in response to stimulation.
Properties of graded potentials.
Can be depolarizing or hyperpolarizing.
A stronger stimulus produces a larger graded potential.
Graded potentials get smaller the farther they travel (Decremental spread):
>> Charge ‘leaks out’ of membrane!
DO NOT LEARN THIS !!!!!
NEUROSCIENCE 4 (page 1 of 3)
The Action Potential
The Ionic Basis of the Action Potential
Key concepts
•Permeability depends on channel state (open or closed)
•When Pion increases the ion crosses the membrane down its electrochemical gradient.
•This moves the membrane potential toward the equilibrium potential for that ion.
***Changes in membrane potential during the Action Potential are NOT due to ion pumps*****
Action potential: amplitude: up to 100 mV change. Size depends on neuron type
duration: a few ms (1ms = 0.001 s). Depends on neuron type (1-100 ms).
Equilibrium potential for Na
1) Resting potential
Equilibrium potential for K
Five parts
1) Resting membrane potential. PK >> PNa, therefore membrane potential nearer equilibrium
potential for K than that for Na
Voltage-gated Na channels and Voltage-gated K channels
Na Channel activation gate closed
Na Channel inactivation gate open
K channel closed
2) The stimulus depolarizes the membrane potential (moves it in the + direction).
This part of the action potential is also called the “foot”. Its shape is exaggerated in the diagram.
3) Upstroke phase. PNa increases because the Voltage-gated Na channels open quickly. The
upstroke starts when the membrane potential reaches the threshold potential.
Na ions enter the cell down their electrochemical gradient.
PK also increases as the Voltage-gated K channels start to open, but this is slower.
K ions leave the cell down their electrochemical gradient, but fewer than Na ions entering.
Net effect: Membrane potential moves toward the Na equilibrium potential (more Na IN than K OUT!!)
Voltage-gated Na channels and Voltage-gated K channels
Na Channel activation gate open
Na Channel inactivation gate open
K channel closed
4) Repolarization phase.
PNa decreases because the Voltage-gated Na channels inactivate. Na entry stops.
PK increases as the Voltage-gated K channels remain open.
K ions leave the cell down their electrochemical gradient.
Net effect: Membrane potential moves toward the K equilibrium potential
During Repolarization (early)
Voltage-gated Na channels and Voltage-gated K channels
Na Channel activation gate open
Na Channel inactivation gate closed - ↓ Perm. to Na
K channel open
Absolute refractory period: Voltage-gated Na channel cannot open (inactivation gate reders it
insensitive to Voltage!!!)
Stimulus, even if stronger than usual, does not trigger an Action Potential
Repolarization (late)
Voltage-gated Na channels and Voltage-gated K channels
Na Channel activation gate closed
Na Channel inactivation gate closed
K channel open
Absolute refractory period: Voltage-gated Na channel cannot open
5) After-hyperpolarization phase. PK is greater than at rest because the Voltage-gated K channels
are still open. K ions continue leaving the cell down their electrochemical gradient.
Membrane potential moves closer to the K equilibrium potential until the Voltage-gated K channels
close. Then the membrane potential returns to the resting potential.
Voltage-gated Na channels and Voltage-gated K channels
Na Channel activation gate closed
Na Channel inactivation gate open
K channel open
Relative refractory period: a stronger than normal stimulus is needed to open the Voltage-gated Na
channel
Na channels in resting state, but K channels are open
!!!!!! DOES NOT OCCUR IN ALL CELLS !!!!!!
Summary of time-course of changes in Permeability to Na and to K during the Action potential:
Na equilibrium
potential
+30
30
Permeability
Membrane potential
Membrane
potential
(mV)
20
10
PNa
PK
0
-70
0
2
4
K equilibrium
potential
Time (ms)
Regenerative Relationship between PNa and Membrane Potential
•Threshold: change in membrane potential required to open voltage-gated Na channels.
•All-or-Nothing” nature: once threshold has been reached a full size action potential is produced.
•Refractory state: unresponsive to stimulus
Initially depolarization is caused by an event outside the cell (stimulus such as transmitter binding to
receptor, etc).
If less than threshold, graded potential returns to Resting potential.
Once threshold is reached the cycle continues.
Positive feedback behaviour. Depolarisation causes Opening of Voltage-gated Na channels causes
increase in Na Permeability causes Increase Na entry into cell causes depolarisation causes…etc,etc
Self-regenerating process or All-or-Nothing Response: once threshold is reached a full sized action
potential is produced
The cycle continues until the Voltage-gated Na channels inactivate which means they close and
become Voltage- insensitive.
The membrane remains in a refractory (unresponsive) state until the Voltage-gated Na channels
recover from inactivation and become Voltage-sensitive again.
Propagation of the Action Potential:
Local current flow
depolarizes new
adjacent region toward
threshold
Direction of propagation of action potential
Remainder of axon at resting
potential
New active area
at peak of action
potential
Old active region
returning to resting
potential
New adjacent
area at resting
potential
Ion movements during the action potential
•Na ions enter the cell, and K ions leave the cell.
•BUT only a very small number of ions cross the membrane and change the membrane
potential.
•The concentration change is extremely small, less than 0.1%
**Ion pumps are NOT directly involved in the ion movements during the Action Potential**
>> e.g. Na/K pump: Between action potentials Na/K pump returns ions that moved durin AP
Action potential travels quickly
Velocity range in mammals axons:
Large diameter, myelinated axons 120 m/s
Small diameter, non-myelinated axons 1 m/s
Axon diameter and myelination affect conduction velocity
Conduction velocity
•Increases with axon diameter because of the electrical properties (less resistance to current flow inside
the large diameter axon, etc)
•Is higher in myelinated than non-myelinated axons of the same diameter because of electrical
properties (action potentials only occur at nodes of Ranvier, etc).
>Conduction velocity is reduced by factors that:
• Reduce axon diameter (regrowth after injury) or
• Reduce myelination. Conduction may be blocked due to extensive localized loss of myelin.
Multiple sclerosis and diphtheria are examples of demyelinating diseases.
• Conduction velocity is also reduced by cold, anoxia, compression and drugs (some anaesthetics).
NEUROSCIENCE 5 (page 1 of 3)
Neurotransmitters
Neurotransmitters:
•
Provide enormous diversity in the variety transmitters (~ 200) and the genes that encode their
receptors (~ 300).
•
Amino acids (e.g. glutamate and gamma amino butyric acid [GABA]), amines (e.g. noradrenaline
and dopamine) and neuropeptides (e.g. opioid peptides).
•
May mediate rapid (µs- ms) or slower effects (ms-s).
•
Vary in abundance from mM to nM CNS tissue concentrations Neurones receive multiple
transmitter influences which are integrated to produce diverse functional responses
Neurotransmitter
Synthesis
Neurotransmitter
Release
ElectroMechanical
Transduction
200µs
REQUIREMENTS:
1) Biosynthesis: Glutamate  GABA ; Glutamic Acid Decarboxylase (GAD)
2) Followed by packageing in Synaptic Vesicles (near Synaptic Cleft)
(a) Action Potential -> Membrane Depolarisation
reaches nerve terminal opening Ca2+ channels.
(b) Ca2+ ions enter terminal and activates neurotransmitter vesicles
(c) Vesicles dock on the presynaptic membrane
(d) Vesicles fuse to membrane and form pore
(e) Transmitter is released by exocytosis
(f) Vesicle is recycled back into the membrane
(g) Vesicle is filled with more neurotransmitter
•
Ca2+
•
Transmitter containing vesicles to be docked on
the presynaptic membrane
•
Vesicular
release of
neurotransmitter
(T)
FILLING
Protein complex formation between vesicle,
T
T
membrane and cytoplasmic proteins to enable
ENDOCYTOSIS
T
vesicle proteins
both vesicle docking and a rapid response to
Ca2+ entry leading to membrane fusion and
exocytosis.
•
ATP
•
Vesicle recycling
Synaptic
Transmission
T
T T
DOCKING
T
T
T
MEMBRANE FUSION
& EXOCYT OSIS
Presynaptic membrane proteins
(a) Quanta Hypothesis – quanta ~ 4-10 thousand molecules of NT
(b) Synaptic Vesiccles – Small Clear-Cored (ACh) 200µs
Large Dense-Cored (Neuropeptides+Proteins) 50ms
RELEASE OCCURS IN RESPONSE TO INCREASED [Ca2+] = 200µM
Fast/Slow
Systems
Fast (milliseconds) acting neurotransmitter systems are Ligand-Gated Ion Channels.
They act in a space of milliseconds and use amino acids as the neurotransmitter
including:
(a) GABA (γ-amino butyric acid)
CNS
(b) Glutamate (Glu)
CNS
(c) Aspartate (Asp)
CNS
(d) Acetylcholine (Ach)
NMJ
Slow acting systems (seconds/minutes) are G-Protein Linked Receptors. They act in
seconds or minutes and use monamines or neuropeptides as neurotransmitters
including (in CNS and PNS):
(a) Acetylchloine (ACh) – muscarinic receptors
(b) Dopamine (DA)
(c) Noradrenaline (NA)
(d) 5-hydroxytryptamine (5-HT)
(e) Neuropeptides – enkaphalin (endogenous opiate)
T
TT
Inhibition/
Excitation
Neurotransmitters can have either an inhibitory or an excitatory effect on the postsynaptic membrane. Inhibition -Inhibitory Post Synaptic Potential (IPSP)occurs when
the membrane potential is moved away from the threshold potential by the
neurotransmitter (usually by increasing permeability to Cl- ions). Excitation Excitatory Post Synaptic Potential (EPSP) occurs when the membrane potential is
moved towards the threshold value (usually by increasing sodium and potassium
permeability).
Diffuse/Precise A diffuse system is one in which the impulse is spread to numerous postsynaptic
neurones (eg some NA, DA systems) whereas a precise system is one where the
impulse is spread to few specific neurones. Modulatory systems affect the cortex,
brain stem and spinal cord and affect arousal, mood, motivation and sleeping.
Receptors
GLUTAMATE RECEPTORS
Na +
Ca 2+
Na +
AMPA RECEPTORS
NMDA RECEPTORS
alpha amino-3-hydroxy-5-methyl4-is oxaz ole propionic acid
N-methy l-D aspartate
Majority of FAST excitatory synapses
Rapid onset, offset and
desensitisation
Slow component of excitatory
transmission
Serve as coincidence detectors
which underlie learning mechanisms
•
An excitatory CNS synapse
is mediated by
GLUTAMATE.
•
Recylcing of GLUTAMATE
by Excitatory Amino Acid
Transporter (EAAT) in
Glial Cell or Pre Synaptic
Nerve terminal.
Abnormal cell firing leads to seizures associated with excess GLUTAMATE in the synapse
Pentameric organisation of the GABA receptor
and pharmacologically important binding domains
GABA
steroids
barbiturates
ß
benzodiazepines
alpha
•
ethanol
SEE TUTORIAL SHEET FOR
DIAGRAM OF GABA SYNAPSE.
Zn
convulsants
Drugs facilitating GABA transmission are:
antiepileptic
anxiolytic
sedative
muscle relaxant
Drug Treatment Drugs acting on GABA receptor to increase affinity for GABA cause:
(a) Sedation, Sleep
(b) Anticonvulsant
(c) Reduced voluntary muscle tone
Drugs acting to block sodium channels are used as antiepileptics since they stop rapid
firing of neurones eg Phenytoin and Carbamazepine. Increased GABAergic action
also helps prevent seizures.
Dopaminergic drugs such as L-DOPA which can pass through the blood-brain barrier
are used to treat Parkinson’s which is due to loss of dopaminergic cells
Tiagabine
INCREASES transmitter availability by blucking GABA transporters (stays in synapse
for longer as it is not taken up and recycled).
Vigabatrin
INHIBITS inactivation of neurotransmitter (GABA transaminase).
Benzodiazapines and Barbiturates
increases activation of receptors (GABAA Receptor)
Epilepsy:
Refers to a disorder of brain function characterized by the periodic and unpredictable occurrence of seizures. A
seizure is the transient alteration of behaviour due to the disordered, synchronous, and rhythmic firing of
populations of brain neurones. The pharmacological agents in current clinical use for inhibition of seizures are
referred to as anticonvulsant or antiepileptic drugs.
Seizures are thought to arise from the cerebral cortex and they can be classified into partial seizures, those
beginning focally at a cortical site, and generalized seizures, those that involve both hemispheres widely from the
outset.
The behavioural manifestations of a seizure are determined by the functions normally served by the cortical site
at which the seizure arises. Thus, for example, a seizure involving the motor cortex is associated with clonic
jerking of the body part controlled by this region of the cortex.
A simple partial seizure is associated with preservation of consciousness, whilst a complex partial seizure is
associated with impairment of consciousness.
Examples of generalized seizures include absence, myoclonic and tonic-clonic seizures.
Neurotransmitters in epilepsy:
Epilepsy is a neurological disorder associated with abnormal neurotransmitter function in the brain. A decrease
in GABA-mediated inhibition or an increase in glutamate-mediated excitation in the brain may result in seizure
activity. Indeed, both glutamate and GABA are thought to play key roles in the brain mechanisms causing
epilepsy in man.
Pharmacological evidence for a role of neurotransmitters in epilepsy
·
Impairment of GABA-mediated inhibition causes seizures in animals e.g. impairment of synthesis,
release (tetanus toxin) or postsynaptic action (bicuculline, picrotoxin).
·
Enhancement of GABA-mediated inhibition leads to seizure suppression e.g. central (i.c.v.)
administration of GABA or inhibition of the GABA metabolizing enzyme GABA-T (vigabatrin).
·
Many clinically useful anticonvulsant drugs are known to act, at least in part, by potentiating central
GABA-mediated inhibition e.g. benzodiazepines, phenobarbital (see Section 3).
·
Central (i.c.v.; focal) administration of glutamate or glutamate receptor agonists causes seizurelike activity in animals.
·
Glutamate receptor antagonists are anticonvulsant in experimental models of epilepsy.
·
Some therapeutically effective anticonvulsant drugs act partly by blocking glutamate-mediated
excitation in the brain e.g. phenobarbital.
Biochemical evidence for a role of neurotransmitters in epilepsy
·
Cobalt-induced seizures in rodents are associated with  glutamate release and with  GABA
concentration,  GAD activity and  GABA uptake (probably reflecting GABA neurone loss) at the seizure focus.
·
Audiogenic seizures in mice (DBA/2 mice) are associated with  glutamate receptor binding in
the brain and with  GABA release from depolarized brain slices.
NEUROSCIENCE 6 (page 1 of 4)
The Central Nervous System
Divisions:
The CNS is divided into the following major divisions:
(a) Spinal Cord – controls reflex sensori-motor functions and autonomic function
(b) Brainstem (medulla, pons, midbrain) – controls vital functions (eg breathing)
(c) Cerebellum – controls co-ordination of movement
(d) Diencephalon (thalamus, hypothalamus) – interfaces CNS, ANS, endocrine
(e) Cerebral hemispheres (cortex, ganglia) – all functions
Define the functions of the dorsal and ventral horns of the spinal cord and how the dorsal and
ventral roots and spinal nerves relate to them:


Ventral horn contains cell bodies of somatic motor neurons and motor nuclei (carries motor
signals out to body); exits spinal cord to form the ventral root, then combines with the dorsal
root to form the spinal nerve
Dorsal horn contains autonomic and somatic sensory nuclei (receives sensory information
from the Body)
Define the 3 components of the brainstem and state the main functions of the brainstem:
Midbrain, Pons, Medulla oblongata; the brainstem is a netlike region of interspersed grey and white
matter; medulla contains sensory and motor neurons, many nuclei –



affiliates with 5/12 cranial nerves, the cardiovascular centre and part of the respiratory centre;
Pons is a bridge that connects the cerebellum by transverse neurons and are also part of the
sensory and motor tracts, it is also involved in the respiratory centre;
Midbrain contains tracts and nuclei, contains neurons for muscle activity, input from proprioceptors
Define the functions of the 2 main structures of the diencephalons:

Thalamus – relay between lower structures and cerebral cortex

Hypothalamus – control of homeostasis, interface between CNS, ANS and endocrine system
State the functions of the basal ganglia and cerebellum:

Cerebellum - coordinates movement (CANNOT INITIATE IT)

Basal ganglia – controls movement
(TOGETHER THEY :regulate posture and balance)
Lateral aspect of left cerebral hemisphere - Cortical lobes:
Explain the structure and functions of the meninges:
Cranial meninges protect and cover the brain and are continuous with
spinal meninges
>> Dura mater – tough membrane attached to bone or forming partitions
(dural folds) with venous sinuses in their margins
>> Arachnoid membrane – thin membrane attached to the underside of
the dura
>> Pia mater – delicate membrane closely adherent to the surface of
brain and spinal cord
Explain the relationship between the spinal segments, spinal nerves and vertebrae and state at
what level a lumbar puncture can be performed safely:
Spinal Cord
The spinal cord has various spinal and vertebral levels with nerves arising from each.
There are 31 pairs of spinal nerves:
(a) Cervical
(C1 – C8)
08
C1-7 above; C8 below
7
(b) Thoracic
(T1 – T12)
12
below corr. Vert.
12
(c) Lumbar
(L1 – L5)
05
below corr. Vert.
5
(d) Sacral
(S1 – S5)
05
below corr. Vert.
5
(e) Coccygeal Nerve
01
between vertebrae
2
Nerves 31
Vertebrae 29
Lumbar puncture between L3/L4 or L4/L5 NOT L2 OR ABOVE
Spinal nerves leave the intervertebral foramen between the named vertebrae the immediately superior
vertebrae
Identify the components of the ventricular system and relate them to the divisions of the CNS:
>> Lateral ventricle relates to the cerebral hemisphere (1 in each hemisphere)
>> 3rd ventricle relates to the diencephalon (in the middle of the diecephalon)
>> Aqueduct relates to the midbrain
>> 4th ventricle relates to the pons and medulla at the front and the cerebellum at the rear
>> Central Canal goes through the centre of the sinal cord for almost the entire length.
Define herniation as applied to the brain and explain its clinical significance:
Herniation is displacement of brain tissue by either a tumour or bleed; a space-occupying
lesion may cause herniation of brain tissue from one compartment to another
Explain the composition, circulation and functions of CSF
The CSF:

Contains fewer cells, less protein, less K+ and Ca+ and higher Mg+ and Cl- than blood;

A colourless liquid that protects the brain and spinal cord from chemical and physical injury;

Carries oxygen, glucose and other necessities from the blood to the neurons and Neuroglia;

Circulates through the subarachnoid space, around the brain and spinal cord, and through the
ventricles within the brain and spinal cord;

It is produced in the choroids plexuses, networks of capillaries in the walls of the ventricles that
filter and secrete into the blood plasma;

Ependymal cells cover these capillaries and their tight junctions form the blood-CSF barrier
Volume is 80-150ml, Flow Rate is 500ml/day
Define hydrocephalus, its pathology and outline how it may be treated:

Hydrocephalus is caused by elevated CSF pressure; can arise when drainage of the CSF
from the ventricles is compromised;
o 2 types – communicating (all ventricles affected) and non-communicating (not all
affected)

Signs and symptoms; child – increased head circumference, irritability, loss of upward gaze;
adult – headache, drowsy and blackouts

Treated by: draining excess CSF, or by inserting a shunt from the lateral ventricle to the vena
cave or abdominal cavity
Define meningitis and its pathology, distinguishing between viral and bacterial aetiology:
Meningitis is the infection of the pia mater and subarachnoid space;
symptoms are headache, fever, tiredness and irritability; confusion, drowsiness, neck stiffness; rash in
75%
Bacterial meningitis –
CSF is TURBID, Hi WBC count (neutrophils), glucose level is low
Viral meningitis –
CSF is normal, any increase in WBC is predominantly lymphocytes; found in
HIV patients, mumps/glandular fever
Distinguish between an epidural and subdural haemorrhage:
Epidural/Extradulral:
Usually due to a damaged meningeal artery between the skull and the dura after a head trauma.
>> Arterial – High pressure – Quicker development of Lesion and Symptoms
Subdural:
Usually due to a damaged veinbetween the dura and the arachnoid membrane.
>> Venous – Lower Pressure – Slower development of Lesion and Symptoms.
BOTH can cause a space occupying lesion in the confined space of the cranium and hence
neurological deficits
Inferior aspect of brain
Inside of base of skull
NEUROSCIENCE 7 (page 1 of 2)
The Peripheral Nervous System
PNS
The Peripheral Nervous System consists of the nerves emerging from the brain and spinal cord
which innervate the peripheral organs. Axons are found in bundles; axon is surrounded by the
endoneurium, which are bundled into fascicles surrounded by perineurium, which are bundled into
whole nerves surrounded by epineurium
>> NEURONS: cell bodies are located either in CNS (motor neurons) or in peripheral ganglia; axons
project towards targets.
>> GLIAL CELLS: Schwann cells and satellite glial cells
Divisions
The PNS is divided into efferent and afferent divisions, motor neurons/ANS neurons
and sensory neurons respectively:
(a) Efferent – responsible for transmission of information out of the CNS to effectors
(i) Somatic motor neurons (innervating skeletal muscle)
(ii) Autonomic neurons (innervating glands and viscera)
(b) Afferent – responsible for transmitting information from recpetors to the CNS
(i) Sensory neurons (innervating skin, joints, viscera)
Spinal Nerves
A typical spinal nerve supplies one region of the body (a dermatome of skin)
They consist of: (a) a ventral root (motor)
(b) a dorsal root (sensory)
(c) a dorsal root ganglion where they meet
The spinal nerves also divide into several branches called rami
These are:
(a) the dorsal ramus (innervating skin and muscle of the back)
(b) the ventral ramus (innervating skin, chest muscles, limbs, pelvis)
(c) the rami comunicantes(sympathetic neurons innervating viscera)
There are 31 pairs of spinal nerves (SEE p1 Neuroscience 5)
The upper limbs are supplied by nerves C5 to T1 via the Brachial plexus
The lower limbs are supplied by nerves L2 to S2 via the Lumbo-sacral plexus
Each nerve also supplies half the adjacent dermatome so that a lesion in one nerve will not
result in complete loss of sensitivity (anaesthesia) but rather a decrease in sensitivity
(hypoaesthesia) Knowing which spinal nerve supplies which area of skin means that loss of
sensitivity in an area can point to the damaged region of the spinal cord



The ventral rami of the spinal nerves (except T2-T12) form network of nerves called plexuses.
The brachial and lumbo-sacral plexuses supply the innervation of the upper and lower limbs
respectively
In a plexus, the nerve fibres (axons) of different spinal nerves are recombined to form a peripheral
nerve. Therefore, peripheral nerves contain axons from different spinal nerves.
Peripheral nerve injury or nerve compression may result in complete sensory and motor loss over the area
supplied by the nerve. Some examples of vulnerable nerves:
o ulnar nerve: the nerve lies near the surface of the elbow and is easily damaged resulting
in wasting of hand muscles and loss of sensation over the little finger.
o median nerve: may become compressed and damaged as it passes a narrow tunnel in
the wrist, resulting in wasting of the thumb muscles (carpal tunnel syndrome)
o sciatic nerve: injured in the buttock by badly placed injections, resulting in paralysis of
the foot and loss of sensation over the front and back of the lower leg and foot.
Peripheral
Nerves
Each peripheral nerve forms bundles called fascicles which divide along its length
supplying various regions of the body. Each part is surrounded by a connective tissue
sheath: (a) epineurium
loose connective tissue surrounding the whole nerve
(b) perineurium dense connective tissue surrounding a fascicle
(c) endoneurium loose connective tissue surrounding individual nerves
Nerve fibre classification

Nerve fibres can be classified on the basis of structural (e.g. size and whether or not the fibres
are myelinated) and functional criteria (e.g. conduction velocity).

In general, the larger the diameter the faster the axonal conduction velocity

Peripheral nerves usually contain a mixture of fibres of different diameter and conduction
velocity (CV).

The compound action potential recorded from a nerve contains several peaks reflecting the
CV of different classes of nerve fibres (see diagram below)
Myelinated fibres

Schwann cell membrane wraps around a single axon in a spiral fashion forming up to 100
layers of myelin. Each cell covers only a small segment of the axon (internode)

The junction where two Schwann cells meet is devoid of myelin (node of Ranvier)

Saltatory conduction: conduction velocity is faster in myelinated fibres because the action
potential (AP) jumps from one node to the next
Unmyelinated fibres

Several nerve fibres lie within invaginations of the Schwann cell

Axonal diameter (~1 µm) is much less than that of myelinated axons (1.5-20 µm)

Continuous conduction: AP causes depolarisation of immediately adjacent membrane.
If a peripheral nerve is damaged the can be regenerated by this process:
(a) Within 48hrs the axon and sheath beyond the crush/cut is phagocytosed
by macrophages (Wallerian degeneration)
(b) The cell bodies undergo metabolic changes (Chromatolysis)
(c) The proximal axon find Schwann cells and endoneurial sheaths
(d) Failure causes trapped axons called a neuroma
(e) Otherwise regeneration of the axon is 2-5 mm per day and will be
complete from 1 month to 1 year
Diagnostic
Techniques
(a) Nerve Conduction Velocity can determine if peripheral neuropathy is present, and
whether it is demyelinating or axonal.
(b) Nerve biopsy of a small peripheral nerve can be used to study pathogenesis of the
disease.
NEUROSCIENCE 8 (page 1 of 3)
The Autonomic Nervous System
Functions
The autonomic nervous system (ANS) is the part of the nervous system that controls
involuntary activity (eg homeostasis) Examples include:
(a) Blood Pressure Regulation
(b) Respiration Regulation
(c) Gastrointestinal Motility
(d) Temperature Regulation
It is divided into two separate systems:
(a) Parasympathetic (“Eat and Sleep” functions) Discrete and specific
(b) Sympathetic (“Fight or Flight” functions) Diffuse stimulating whole body
Baroreceptor
Reflex
This maintains blood pressure. Increased arterial pressure stimulates baroreceptors
which increase afferent nerve activity which in turn decreases sympathetic activity
which leads to decreased heart rate and vasodilation which decreases blood pressure
Fight or Flight
Reflex
This is a mass Sympathetic discharge in response to stress or alarm and induces:
(a) increased blood pressure
(b) increased blood flow to muscle
(c) decreased blood flow in other areas (eg splanchnic bed)
(d) increased blood glucose
(e) increased respiration
Sympathetic
Anatomy
The sympathetic nerves are from T1 to L3 down the spinal cord
There are many more post-ganglionic nerves than there are pre-ganglionic. This
causes diffuse sympathetic effects.
ParasympatheticThe parasympathetic nerves are from either the cranial or sacral outflow.
Anatomy
There are five main ganglia:
(a) Occulomotor nerve (IIIrd Cranial)
(b) Facial nerve (VIIth Cranial)
(c) Glossopharyngeal nerve (IXth Cranial)
(d) Vagus nerve (Xth Cranial)
(e) Splanchnic nerve
Describe the sympathetic and parasympathetic pathways and their central/spinal
connections
Sympathetic preganglionic neurons have their soma in the lateral horns of the grey matter
in the 12 thoracic segments and first 2 lumbar segments. Ganglia are either sympathetic
trunk ganglia or prevertebral ganglia, servicing organs above and below the diaphragm
respectively; they are close to the CNS and so preganglionic sympathetic neurons are
usually short; preganglionic neurons can also synapse with the adrenal medulla which
secretes products into the bloodstream – it is a neuroendocrine organ
Parasympathetic preganglionic neuron soma are located in the nuclei of the 4 cranial
nerves in the brain stem, and in the lateral grey horns of S2-S4 (sacral); ganglia are
terminal, located close to or within the wall of the visceral organ – the preganglionic
neurons are therefore long
Identify the neurotransmitter substances released at different levels within the autonomic
nervous system

Parasympathetic solely use ACh;

Sympathetic use ACh at the ganglion then NA/NE at the effector;
o preganglionic fibres to the adrenal medulla use ACh;
o sympathetic fibres to sweat glands however use ACh as both the pre
and post ganglionic neurotransmitters
Sympathetic:
(i) typical
Effector cell
Pre-ganglionic fibre
ACh
Nicotinic receptor
Post-ganglionic fibre
NA
Adrenoceptor ( or )
(ii) adrenal medulla
Adrenaline +
noradrenaline ( 20%)
are transported by the
blood stream to their
receptors
Pre-ganglionic
fibre
AC
Nicotinic receptor h Chromaffin
(a)
Parasympathetic
Pre-ganglionic fibre
ACh
Nicotinic receptor
Postganglionic
fibre
cell
Effector cell (iii) exceptions
ACh
Muscarinic receptor
Pre-ganglionic
fibre
AC
h
Nicotinic receptor
Post-ganglionic fibre
AC
h
Effector cell
(e.g. sweat
gland)
Muscarinic receptor
Describe the biosynthesis and metabolism of ACh, NA and A

ACh is formed from acetyl-CoA and choline, which, via the enzyme choline acetyl
transferase, produces ACh and CoA; on the receptor ACh is broken down by
acetylcholinesterase into acetate and choline, which is transported back into the
pre-synaptic bulb and reused

NA is formed from the amino acid tyrosine → DOPA (tyrosine hydroxylase); →
dopamine (DOPA decarboxylase; → NA (dopamine β hydroxylase); from the
receptor NA is actively taken back into the pre-synaptic bulb where it is
metabolised by Monoamine oxidase A. Or it is taken into Glial Cells and
degraded (COMT). Giving MOPEG and VMA which are conjugated
(glucuronide/sulphate) and excreted.

A is formed from NA via phenylethanolamine methyl transferase
Describe the influence of the sympathetic and parasympathetic nervous systems on
principal organs/systems of the body
Organ/System
Effect of sympathetic
Effect of parasympathetic
Cardiovascular
↑ - Increases cardiac output
↑ - Slows HR; vasodilatation of
(ionotropic effect SV and
certain blood vessels to discrete
chronotropic effect HR);
glands and organs (e.g. willy)
increased TPR
↓ - vasodilatation (due to
decreased sympathetic tone)
Gastrointestinal
Decreases motility and tone;
Increases motility and tone;
stimulates contraction of
relaxation of sphincters; stimulates
sphincters; inhibits secretory
secretory activity
activity
Eye muscles
Relaxes ciliary muscle, lens
Contracts ciliary muscle, lens
flattens for distant vision;
bulges for near vision; contracts
contracts radial muscle (pupil
pupillary sphincter (pupil
dilation)
contraction)
Bladder
↓ - relaxation of the sphincter
Main influence; ↑ - contraction of
vesicae (via hypogastric nerve)
detrussor muscle and relaxation of
sphincter vesicae (via pelvic nerve)
Lungs
↑ - dilates bronchi and
bronchioles (↑ O2 delivery)
Willy
↑ - penile flaccidity; ejaculation
↑ - boner
Describe the concept of dual innervation
Most organs have both sympathetic and parasympathetic innervation each of which
usually has an opposite effect (Control of HR and Bronchiole Diameter). There is also a
certain amount of Autonomic tone which contrivutes to the normal firmness of a
tissue/organ.
Give an example of an autonomic reflex – pupil constriction in response to light
In the eye there are two sets of muscles, the circular and the radials.
In moments of high drama the sympathetic fires and contracts the Radial muscles (lens
flattens for distant vision) - pupil dilatation. Mydriasis - ATROPINE
In quieter times the parasympathetic is dominant and contracts the Circular muscles (lens
bulges for near vision) - pupil contraction. Miosis – Pilocarpine.
Retinal photoreceptors detect the light; optic nerve (cranial II sensory) transmits a signal to
the pretectal nucleus; then to the Edinger Westphal Nucleus; signal then transmitted along
the occulomotor nerves (cranial III motor) to the ciliary ganglia causing parasympathetic
innervation of the pupillary sphincter
Classify the cholinergic receptors within the ANS

Nicotinic receptors on post ganglionic fibres and Chromaffin cells of the nicotinic
receptor; transmission is fast as these are ligand gated ion channels;

Muscarinic receptors on receptor organs; transmission is relatively slow and is
mediated by G-protein coupled receptors produce a magnifying effect and are
found on a) effector organs with parasympathetic innervation, b) sweat glands,
which have sympathetic innveration).
Classify the adrenergic receptors within the ANS
Adrenoceptors are primarily found on the effector cells of the sympathetic nervous system.
They are classifid into alpha and beta subclasses depending on the specific responses
they elicit and the selective binding of drugs that activate or block them.

Alpha examples – radial muscle in eye, salivary glands, sphincter muscles of
stomach and bladder.

Beta examples – cardiac muscle, smooth muscle of airways (qv asthma), liver.
These are also G-protein coupled
Generally speaking Alpha1 and Beta1 receptors generally produce excitation whilst Alpha2
and Beta2 receptors generally cause inhibition. There is a third type, Beta3, which are
found only on brown adipose tissue and bring about thermogenesis.
Describe how autonomic activity can be estimated with physiological and biochemical
examples
Monitoring blood pressure and heart rate; responses to heat (i.e. no sweat); control of
organs e.g. constipation, emptying of bladder, sexual function
Sympathetic activity monitored by plasma NA and A levels
Postural hypotension, tachycardia, loss of pupil reflexes, loss of pulse response to forced
expiration, no sweating or pupil reflexes on the injection of certain agents. Take blood
pressure in different positions to check postural hypotension.
CLASSIFY DISORDERS OF THE AUTONOMIC NERVOUS SYSTEM WITH EXAMPLES OF
LOCALISED AND GENERALISED DISORDERS.
Disorder may be a systemic one or confined to a particular region; for example in
Pheochromocytoma, a mass in the adrenal gland, which causes excessive release of adrenaline
and noradrenaline and causes headaches, palpitations, raised blood pressure, tachycardia and
other adrenergic effects. Or the condition may be confined to a particular region, such as with
trauma patients who have damaged their spine in a certain area and lost autonomic function at
nerves below that point.
DESCRIBE THE MAIN ABNORMALITIES IN AUTONOMIC FAILURE.
Postural hypotension, tachycardia, impotence, ejaculatory failre, incontinence, constipation,
diarrhoea, inability to sweat, dry mouth and eyes, Horner’s syndrome, held dilatation or
constriction, sluggish or absent light response.