Synapses and neuromuscular control

What are the 2 main types of synapses?

1. Electrical - direct current flow through gap junctions

2. Chemical - electrical signal converted to chemical signal via neurotransmitters

What are the key components of electrical synapses?

• Gap junctions containing intercellular channels

• Made of connexin or innexin proteins

• Allow direct electrical communication between cells

What are the main characteristics of chemical synapses?

• Neurotransmitters stored in synaptic vesicles

• Release triggered by calcium influx

• Transmitters act on specific receptors on postsynaptic cell

• One-way communication

• More complex and modifiable than electrical synapses

Describe the synthesis and storage of ACh

• Synthesised from choline and Acetyl-CoA by choline acetyltransferase

• Packaged into synaptic vesicles

• Stored in presynaptic terminal until release

What triggers ACh release at synapses?

• Action potential arrives at axon terminal

• Voltage-gated Ca2+ channels open

• Ca2+ influx triggers vesicle fusion

• ACh released into synaptic cleft

How does ACh act at the neuromuscular junction?

• Binds to nicotinic ACh receptors

• Each receptor requires two ACh molecules

• Opens non-specific cation channels

• Allows Na+ and K+ passage

• Net Na+ influx causes muscle fibre depolarisation

How is ACh inactivated?

• Broken down by acetylcholinesterase (AChE)

• Rapid termination of synaptic transmission

• Choline recycled back to presynaptic terminal

What is the main function difference between autonomic and somatic nervous systems?

• Autonomic controls involuntary actions

• Somatic controls voluntary actions

How do neurotransmitter systems differ between autonomic and somatic systems?

• Autonomic uses both ACh and noradrenaline

• Autonomic has both nicotinic and muscarinic receptors

• Somatic uses only ACh with nicotinic receptors

What is the key structural difference between autonomic and somatic pathways?

• Autonomic has two-neuron pathway through ganglia

• Somatic has single motor neuron pathway

What is Myasthenia Gravis?

• Autoimmune disorder affecting neuromuscular junction

• Antibodies attack nicotinic ACh receptors

• Causes muscle weakness and fatigue

• Treated with acetylcholinesterase inhibitors

• Affects 15-20 per 100,000 people

What is Lambert-Eaton Myasthenia Syndrome (LEMS)?

• Presynaptic disorder

• Antibodies attack Ca2+ channels

• Reduces ACh release

• Causes weakness in legs and eye muscles

• Often associated with lung cancer

What are Congenital Myasthenic Syndromes?

• Genetic disorders affecting neuromuscular transmission

• Over 30 genes implicated

• Can affect:

  • ACh receptor function

  • ACh synthesis

  • Acetylcholinesterase function

• Inherited in autosomal dominant or recessive patterns

What characterises Alzheimer’s at a synaptic level?

• Affects multiple synaptic functions:

  • Synapse formation (APP, Aβ, Tau)

  • Synaptic transmission

  • Active zone function

  • Spontaneous release

• Multiple proteins involved (APP, Aβ, BACE1, Presenilin, ApoE4

How does Parkinson’s affect synapses?

• Impairs:

  • Dopamine release

  • Synaptic stability

  • Active zone function

  • Synaptic transmission

• Multiple proteins involved: SOD-1, TDP-43, FUS

Describe depression’s relationship to neurotransmitters

• Involves imbalance in monoaminergic and cholinergic pathways

• Lower activity of noradrenaline, dopamine and serotonin

• Relative overactivity of cholinergic synapses

• Affects limbic system (amygdala, cingulate gyrus, hipppocampus)

What are the main treatments for despression?

• Tricyclic antidepressants (block noradrenaline reuptake)

• SSRis (block serotonin reuptake)

• MAO inhibitors (prevent monoamine breakdown)

• All aim to increase monoamine levels at syanpses

What are the structural components of gap junctions?

• Composed of connexons (hemichannels)

• Each connexon made of 6 connexin proteins

• Direct cell-to-cell communication

• Allow passage of ions and small molecules

Describe the functional properties of gap junctions

• Bidirectional communication

• Fast transmission

• Electrical coupling between cells

• Can be regulated by calcium and pH

• Important in synchronised cell activity

What are the main classes of neurotransmitters?

• Small molecules (ACh, amino acids, monoamines)

• Neuropeptides

• Purines (ATP)

• Gases (NO, CO)

What is the major excitatory neurotransmitter in the CNS?

Glutamate

What is the major excitatory neurotransmitter in a neuromuscular junction?

Acetylcholine

What is the major excitatory neurotransmitter in the sympathetic system?

Noradrenaline

Where in the nervous system is the excitatory neurotransmitter Substance P used?

CNS and PNS, in pain and modulation

What is the primary inhibitory neurotransmitter in the CNS?

GABA

What is the main inhibitory neurotransmitter in the spinal cord?

Glycine

Describe the steps of regulated exocytosis

1. Vesicle docking at active zone

2. Vesicle priming

3. Calcium influx

4. SNARE complex formation

5. Vesicle fusion and transmitter release

Explain ACh metabolism in detail

1. Synthesis by choline acetyltransferase

2. Storage in synaptic vesicles

3. Release triggered by calcium

4. Binding to receptors

5. Breakdown by AChE

6. Choline reuptake

What are the characteristics of ionotropic receptors

• Ligand-gated ion channels

• Fast response (milliseconds)

• Direct ion flow

• Example: nicotinic ACh receptor

• Channel opens upon binding

Describe metabotropic receptor function

• G-protein coupled

• Slower response (seconds)

• Second messenger cascades

• Example: muscarinic ACh receptor

• Multiple downstream effects

Detail the structure of nicotinic ACh receptors

• 5 protein subunits

• Forms ion channel

• Non-selective cation channel

• Fast synaptic transmission

How do muscarinic ACh receptors work?

• 5 subtypes (M1-M5)

• G-protein coupled

• Multiple signalling pathways

• Slower responses

• Found in autonomic system

Describe noradrenaline receptor types

• Alpha (α1, α2) receptors

• Beta (β1, β2, β3) receptors

• All G-protein coupled

• Different tissue distributions

• Different physiological effects

How are neurotransmitters inactivated?

1. Enzymatic breakdown

2. Reuptake by transporters

3. Diffusion away from synapse

4. Glial cell uptake

5. Specific mechanisms for each transmitter

Describe neural pathway organisation

• Afferent (sensory) pathways

• Efferent (motor) pathways

• Central integration

• Reflex arcs

• Hierarchical control

Detail efferent somatic pathway structure

• Single motor neuron pathway

• Direct innervation of skeletal muscle

• Uses ACh as transmitter

• Nicotinic receptors only

• Voluntary control

What are the key features of neuromuscular junction anatomy?

• Specialised synaptic terminal

• Junctional folds

• Concentrated ACh receptors

• Schwann cell coverage

• Precise alignment of pre- and post-synaptic elements

Explain synaptic transmission at the neuromuscular junction

1. Action potential arrival

2. Calcium influx

3. ACh release

4. Receptor binding

5. End-plate potential generation

6. Muscle contraction

What are common neurological disorders affecting synapses?

• Alzheimer’s

• Parkinson’s

• ALS

• MS

• Huntington’s

List the main types of myasthenic disorders

1. Autoimmune (MG, LEMS)

2. Congenital (CMS)

3. Drug-induced

4. Lambert-Eaton Syndrome

5. Botulism

Describe autoimmune myasthenic disorders in detail

• Myasthenia Gravis (receptor antibodies)

• LEMS (calcium channel antibodies)

• Variable muscle weakness

• Fluctuating symptoms

• Treatment with immunosuppression

What are the main congenital myasthenic disorder?

• ACh receptor deficiency

• Choline acetyltransferase deficiency

• AChE deficiency

• Genetic inheritance

• Present from birth

List the types of depression

• Endogenous (internal cause)

• Exogenous (external cause)

• Monopolar (major depression)

• Bipolar (manic depression)

• Seasonal affective disorder

What causes depression at the synaptic level?

• Monoamine imbalance

• Reduced serotonin

• Reduced noradrenaline

• Reduced dopamine

• Cholinergic overactivity

List all major depression treatments

1. SSRIs (Prozac, Zoloft)

2. Tricyclic antidepressants

3. MAO inhibitors

4. Psychotherapy

5. ECT in severe cases

How do antidepressant medications work?

• Block neurotransmitter reuptake

• Increase synaptic monoamines

• Modify sensitivity

• Affect neural plasticity

• Takes weeks for full affect

What are the key neurotransmitter systems in depression?

• Serotonergic

• Noradrenergic

• Dopaminergic

• Cholinergic

• GABA-ergic

Describe the genetic factors in depression

• Multiple genes involved

• Neurotransmitter-related genes

• Receptor genes

• Environmental interactions

What are the amin symptoms of depression?

• Mood changes

• Sleep disturbance

• Appetite changes

• Loss of interest

• Cognitive impairment

What can make SSRIs preferabable?

Fewer side effects compared to others

What can make Tricyclics preferable?

They have a broader action on multiple neurotransmitters

What can make MAO inhibitors preferable?

They are an option for patients with dietary restrictions and atypical depression

What can make SNRIs preferable?

Dual-action (depression and anxiety)

What are the latest developments in depression treatment?

• Ketamine therapy

• Deep brain stimulation

• Novel drug target

• Personalised medicine

• Combined approach