Nervous System: General and sensory

Question 1

Describe the various levels of the CNS

Note the basic functions performed at each level

Answer 1

1. Spinal cord
   
   • Acts as a conduit of sensory information from the periphery to the brain
   • Transmits signals from the brain to the periphery
   • Organises complex local functions
     
     • Urination
     • Reflexes - including withdrawal and muscle tone against gravity
     • Gastrointestinal movements
     • Regulation of vascular reflexes
2. Lower brain / subcortical
   
   • Primary control centre of many “sub-conscious activities
     
     • Respiration
     • Blood pressure regulation
     • Control of equilibrium (with cerebellum)
     • Feeding reflexes - including initiation of salivation
     • Many emotional patterns including anger, excitement, sexual arousal, reaction to pain
3. Higher brain / cortical
   
   • Major storehouse of information
   • Controls precision of responses from the subcortical regions
   • Thought processing

Question 2

Briefly describe the process by which a presynaptic neuron can pass a message to the post-synaptic membrane through an electrical channel.

Not the important anatomical structures and provide examples

Answer 2

• Transmission through the neuronal synapse can occur via electical channels or via chemical messengers (neurotransmitters)
• Electrical transmission requires a narrow synapse with direct ion channels called gap junction channels
  
  • Gap junction channels allow passage of ions directly from one cell interior to the next
  • The AP can be directly transmitted to the next cell
  • Bi-directional transmission can occur
  • Multiple cells with sub-threshold potentials can be detected in a cluster of inter-connected neurons
• This mechanism of transmission is important in the smooth muscle and within cardiac muscle cells

Question 3

Describe the process by which a pre-synaptic neuron passes a message to a post-synaptic membrane via a chemical pathway.

Note the important anatomical structures and provide examples.

Answer 3

• Using a chemical pathway, the transmission of a nerve action potential to a post-synaptic membrane requires release of a neurotransmitter from the pre-synaptic terminal
  
  • The action potential reaching the pre-synaptic terminal causes opening of calcium channels and calcium inflow
  • Calcium binds with protein molecules on the internal side of the membrane called release sites
  • This process enables vesicles containing large amounts of neutrotransmitter to bind with the membrane
    
    • The neurotransmitter is released via exocytosis
• The neurotransmitter must diffuse across the synapse and bind with a receptor on the post-synaptic membrane
• Neurotransmitter binding can then induce either opening of an ion channel (often sodium) or activation of a second messenger system (often coupled to a G protein)

Chemical neurotransmitters allow for uni-directional message transmission.

The release of acetylcholine throughout the parasympathic nervous system or noradrenaline from the SNS are examples of a chemical messenger synapse

Question 4

Describe the major differences between the ion channels and second messenger systems for post-synaptic nerve effects

Answer 4

Ion channels

• Activation of an ion channel in a post-synaptic membrane is rapid
• Direct opening of an anionic channel or cationic channel will directly allow transport of Na⁺ or Cl^- transfer into the cell
  
  • This ionic movement causes excitation (transmission of the AP) or inhibiton of the post-synaptic membrane respectively
• The ionic channels open very briefly and after they close, the post-synaptic cell returns to baseline/normal. ie. there is no lasting change

Second messenger system

• By alteration of the cell interior via a second messenger system, lasting change or prolonged action on the post-synaptic membrane can be effected
• A G-protein coupled system can cause opening of an ion channel with prolonged effect
• Can cause activation of cAMP or cGMP which can alter cellular metabolism
• G proteins can alter cellular enzyme expression
• Gene transcription can be effected via second messenger systems

Question 5

Briefly describe the process of activation of a G-protein second messenger system

Note also how the “message” is terminated

Answer 5

• Initiation of a G-protein messenger system initially requires binding of a neurotransmitter to a receptor protein in the post-synaptic cell membrane
• Binding of the receptor protein exposes a G-protein binding site due to a conformational change
  
  • Cytosolic G protein is then able to bind to the receptor
• The alpha subunit releases bound GDP while binding to GTP
• Simultaneously, the beta and gamma subunits are released from the protein structure
• This process allows the alpha subunit, now bound to GTP, to be released from the receptor and trigger cellular actions such as gene transcription or activation of cellular enzymes
• The action of the G protein is terminated when the GTP is hydrolysed to GDP on the alpha subunit
  
  • This triggers release from the target protein and re-binding with the beta and gamma subunits
  • The protein is inactive when all three subunits are bound together

Question 6

List the possible post-synaptic changes that can lead to an excitatory signal in the post-synaptic neuron

Answer 6

• Opening of sodium channels
  
  • Increases the membrane potential towards zero
  • Can rapidly elicit generation of an AP in the post-synaptic cell membrane
• Reduced conduction through membrane chloride or potassium channels
  
  • Reduced influx of chloride or efflux of potassium helps increase the cell membrane potential
• Alteration of cellular metabolism such that the excitatory membrane receptors increase or inhibitory receptors are decreased

Question 7

List the possible post-synaptic changes that can lead to an inhibitory signal in the post-synaptic neuron

Answer 7

• Opening of chloride channels
  
  • Allows chloride influx and increases the negative charge within the cell
  • Reduced cell membrane potential is stabilising/inhibitory for AP generation
• Increase potassium channel conductance
  
  • Increased potassium efflux leads to reduced positivity within the cell - similar outcome as above
• Activation or inactivation of cellular enzymes
  
  • Increased expression of inhibitory receptors
  • Decreased expression of excitatory receptors

Question 8

List and describe the important characteristics of the most common small molecule neurotransmitters

Answer 8

1. Acetylcholine
   
   • Rapidly synthesised by choline acetyltransferase from acetyl CoA and choline
   • Released by preganglionic nerves of the autonomic nervous system
   • Released by post-ganglionic nerves of the parasympathetic and some sympathetic nerves
   • Predominantly an excitatory neurotransmitter
2. Norepinephrine
   
   • Widespread release from neurons within the brain stem
   • Responsible for controlling ocerall activity of the brain and wakefulness
   • Released by the majority of post-gangionic nerves of the SNS
   • Predominatly excitatory but has inhibitory effects depending on the target organ
3. Dopamine
   
   • Primarily an inhibitory neurotransmitter released by neurons that originate in the substantia nigra
   • Mostly released into regions of the basal ganglia
4. Glycine
   
   • Inhibitory neurotransmitter released at synapses in the spinal cord
5. GABA (gamma aminobutyric acid)
   
   • Secreted by many areas of the spinal cord, cerebellum, basal ganglia and cortex
   • Primarily inhibitory in the developed brain
6. Glutamate
   
   • Excitatory neurotransmitter secreted by sensory nerve terminals entering the CNS
   • Also released in many areas of the cortex
7. Serotonin
   
   • Secreted by neurons that originate in the median raphe of the brain stem - project to many areas of the spinal cord and brain
   • Primarily inhibitory to the dorsal horns and hypothalamus
   • Inhibits transmission of pain sensation
   • Helps control mood and enhance sleepiness
8. Nitric oxide
   
   • Produced and released by diffusion from the presynaptic nerve terminal
   • Minimal interaction with the post synaptic nerve cell membrane but readily diffuses into the cell
   • Primary action on intracellular metabolic function - specific functions are less well known

Question 9

Briefly describe the production and release of neuropeptides.

Note the differences from the small molecule transmitters

Answer 9

• The neuropeptides are produced within the the cell body by ribosomes
  
  • The small molecules are produced within the cytosol of the pre-synaptic nerve terminal
• They are generally formed as an integral part of a larger protein
• Within the golgi, the integral protein is enzymatically cleaved into smaller fragments - the neuropeptide or a precursor
  
  • These are then packaged into minute transmitter vesicles
• These vesicles are then slowly moved to the terminal nerve fibre via axonal streaming
  
  • ​This process may take weeks as the vesicles move at a few cm per day
• Release is in response to AP transmission
• The vesicle is then autolysed and not recycled as for the small molecule vesicles

Question 10

What is the effect of acidosis and alkalosis on the excitability of the neuron.

Provide examples / outcomes

Answer 10

Acidosis

• A decrease in pH greatly depresses neuronal cell excitability
  
  • A decrease towards a pH of 7.0 can result in such depression of neuronal cell activity that coma develops
  • This can be seen with diabetic ketoacidosis or uraemic acidosis

Alkalosis

• An increase in pH will increase the excitability of neurons
  
  • Hyperventilation triggered respiratory alkalosis can lead to epileptic seizures in a predisposed individual

Question 11

Describe the pathophysiological mechanism for reduced muscle activity in myasthenia gravis

Answer 11

• Acquired myasthenia gravis is an immune mediated disorder characterised by development of auto-antibodies against the nicotinic ACh receptor
  
  • This receptor is primarily expressed on the post synaptic membrane of the muscle
• The antibodies lead to complement mediated lysis of the receptors and reduced numbers of receptors
• Due to reduced receptor number, the muscles are less able to respond to release of ACh into the synaptic cleft
• The congenital disease can result from a significant deficiency in the number of ACh receptors, lack of ACh or deficiencies in AChE

Question 12

Describe the pathophysiological mechanism for reduced muscle activity in botulism

Answer 12

• Botulism is caused by the toxin released from clostridium bolulinum bacteria. It is often ingestion of the toxin itself that leads to the clinical disease as opposed to tissue infection with the bacteria
• The botulinum toxin effect an irreversible enzymatic cleavage of SNARE proteins within the pre-synaptic nerve terminal of cholinergic nerves
  
  • These nerves supply both the skeletal muscle and the paraympathetic nerves of the autonomic nervous system
• SNARE proteins are essential for enabling the docking of ACh vesicle to the pre-synaptic cell membrane
• The effects on the skeletal muscle system cause a rapidly ascending lower motor neuron (NMJ) paralysis
• The autonomic effects can contribute to ileus, mydriasis, urine retention, cranial nerve deficits and megaoesophagus
• Recovery occurs over 1-4 weeks and is dependent on the production of new SNARE protein (likely in the ribosomes / golgi with subsequent axonal streaming to re-populate the nerve terminal)

Question 13

Describe the pathophysiological mechanism for reduced muscle activity following elapid snake envenomation

Answer 13

• Varibale mechanisms have been proposed
  
  • Tight binding to the post-synaptic AChR , blocking neuromusclar propogation of the AP
  • Pre-synaptic inhibition of ACh release from the pre-synaptic nerve terminal
• Reduced muscle activity may also occur due to specific toxins that contribute to primary muscle cell damage, reducing the ability of the muscles to activate and work
• Reduced cholinergic activity in the parasympathetic nervous system may also contribute to mydriasis, ptyalism, ileus, dysphagia and facial paralysis (cranial nerve signs are common)

Question 14

Describe the pathophysiological mechanism for reduced muscle activity in ixodid tick paralysis

Answer 14

• Mechanism not certain
• The toxin is present in the female tick saliva and released when the tick attaches and feeds
• The toxin likely interferes with ACh release from the pre-synaptic nerve terminal
  
  • The mechanism for interference likely involves changes to calcium movement
• Autonomic dysfunction is common with the ixodes tick, but does not occur with the American tick (Dermacentor)
  
  • The autonomic signs can include urinary retention, diastolic dysfunction and subsequent pulmonary oedema

Question 15

Describe the pathophysiological mechanism for reduced muscle activity in immune mediated myositis

Answer 15

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Question 16

Describe the pathophysiological mechanism for reduced muscle activity in polyradiculoneuritis

Answer 16

• Evidence strongly supports polyradiculoneuritis to be caused by a type IV immune response, resulting from a shared antigen between the inciting stimulus and the peripheral nervous system
  
  • Campylobacter is the most likely causative organism, though others are possible
• Campylobacter infection triggers the production of antibodies which mistakenly bind to the motor neurons in the ventral horn of the spinal cord or the peripheral nerve roots
• Antibody binding enables T cell mediated damage to the nerve axon or myelin sheath
  
  • Reduced nerve AP transmission reduces release of ACh and markedly diminished muscle motor activity
• Sensory nerves remain intact

Question 17

Explain the effect of carbamate and organophosphate toxicity on the neuromuscular junction

Answer 17

• Carbamates cause reversible inhibition of ACh esterase within the synaptic cleft
• Organophosphates cause irrevesible enzymatic phosphorylation of AChE
• AChE is important in both parasympathetic and sympathetic ganglia, parasympathic muscarinic terminals and nicotinic receptors and the NMJ
• Diminished action of AChE leads to prolonged activity of ACh and repetitive AP generation in the target nerve/muscle
• There is also increased neurotransmitter signalling within the brain
• DUMBBELS - increased parasympathetic signalling
  
  • defecation, urination, miosis, bronchospasm, bronchorrhoea, emesis, lacrimation and salivation
    *

Question 18

Explain the pathophysiological mechanism for the effect of the tetanus toxin

Answer 18

• Tetanus is caused by the tetanus toxin produced by the vegetative form of the clostrium tetanii bacterium
• The toxin is absorbed into the pre-synaptic membrane of the peripheral nerve
• The toxin is then moved retro-axonally towards the spinal cord
  
  • Once in the spinal cord the toxin undergoes transytosis to enter the inhibitory neurons
• Once in the inhibitory neuron the toxin is cleaved (pH and temperature sensitive) to release the light chain
  
  • The toxin light chain is then free to cleave synaptobrevin an important component of the SNARE protein
• SNARE protein inhibition within the inhibitory neurons prevents the exocytosis of GABA and glycine, important inhibtory neurotransmitters within the spinal cord
  
  • This results in increase firing of the alpha-motor neurons - rigidity, muscle contraction and unopposed muscle spasm
• Loss of inhibition of the SNS in the grey matter of the spinal cord can also lead to hypertension, high catecholamines and tachycardia

Question 19

Describe the phenomenon of fatigue at the synapse.

Why and in which circumstances is this important

Answer 19

• The initial stimulation of an excitatory nerve by a neurotransmitter causes AP transmission and stimulation
• With repetitive stimulation, the initial firing of the excitatory nerve is very rapid
• Over milliseconds to seconds, the firing rate to the same stimulatory stimulus reduces
  
  • This reduction in firing rate is called fatigue of synaptic transmission
• This fatigue is especially important in the hyper-excitable state, causing neurons to lose their excitability
• Fatigue likely occurs for a number of reasons:
  
  1. Reduced stores of neurotransmitter in the pre-synaptic vesicles
  2. Progressive utilisation and inactivation of the post-synaptic membrane receptors
  3. Slow development of abnormal ion concentrations within the post-synaptic cell reducing the propensity for AP generation or transmission

This may be a part of the reason for cessation of an epileptic seizure

Question 20

List the major MOTOR neuronal components within the spinal cord

Note the basic structure and action of each

Answer 20

1. Anterior (ventral) motor neurons
   
   • Leave the cord via the ventral nerve roots and innervate the skeletal muscle fibres
   • 50-100% larger than the other neurons
   • Comprise both the alpha and gamma neurons
2. Alpha motor neurons
   
   • Large neurons that branch to supply the skeletal muscle fibres or motor unit
3. Gamma motor neurons
   
   • Smaller motor neurons that supply the smaller intrafusial fibres that are responsible for maintenance of basic muscle tone
4. Interneurons
   
   • Tiny neurons present within all areas of the spinal cord
   • 30 times as numerous as the anterior motor neurons
   • Highly excitable, often with spontaneous activity
   • Large numbers of interconnections provide the circuitry for the intergrative functions of the spinal cord