Evidence-based physiotherapy and rehabilitation resources
Editorial & review policy
Evidence-based physiotherapy and rehabilitation resources
Editorial & review policyHuman Physiology · Excitable tissues
Nerves talk to each other, and to muscle, across tiny gaps called synapses. This is where signals are added up, where drugs and diseases act, and where learning changes the nervous system. It is also where rehabilitation does much of its work.
Part 2 · Excitable Tissues · Chapter 7 of 47
By the end of this page you should be able to:
Every voluntary movement crosses two kinds of synapse: many between neurons in the brain and spinal cord, and one between a motor neuron and each muscle fibre. Diseases such as myasthenia gravis, drugs such as botulinum toxin and baclofen, and the recovery of function after stroke all act at synapses.
Rehabilitation itself is, in large part, a way of changing synapses. Practice strengthens the connections it uses. Understanding that turns “do more repetitions” from habit into a reasoned prescription.
At an electrical synapse, gap junctions connect two cells so current passes directly. Transmission is instant and can go both ways. Such synapses synchronise heart muscle and some groups of neurons.
Most synapses in the nervous system are chemical. The two cells are separated by a cleft about 20–40 nm wide, and a chemical messenger carries the signal across. This is slower, by about half a millisecond, but it allows amplification, inhibition and change with use.
Figure 1 · The chemical synapse
When the impulse reaches the terminal, it opens voltage-gated calcium channels. Calcium entry triggers vesicles to fuse with the membrane and release their transmitter. Transmitter diffuses across the cleft and binds receptors on the postsynaptic membrane.
Some receptors are themselves ion channels (ionotropic) and act within milliseconds. Others act through internal messengers (metabotropic) and produce slower, longer-lasting effects. The signal ends when transmitter is broken down by an enzyme, taken back into the terminal, or diffuses away.
Transmitter is released in packets. Fatt and Katz recorded tiny spontaneous potentials at resting motor nerve endings and showed they were caused by the release of single packets, or quanta [1]. A nerve impulse releases many quanta at once.
An excitatory postsynaptic potential (EPSP) is a small depolarisation, usually from opening channels that let sodium in. An inhibitory postsynaptic potential (IPSP) moves the membrane away from threshold, usually by opening chloride or potassium channels.
A single EPSP at a central synapse is far too small to fire a neuron. Inputs must add up. Temporal summation adds EPSPs arriving in quick succession at one synapse. Spatial summation adds EPSPs arriving at the same time from different synapses.
Figure 2 · Postsynaptic potentials add up
A typical motor neuron receives thousands of synaptic inputs. It fires when the net effect of all of them brings its axon hillock, the trigger zone where the axon begins, to threshold. The neuron is an adding machine, and inhibition is as important to it as excitation.
| Transmitter | Main action | Where it matters to physiotherapy |
|---|---|---|
| Acetylcholine | Excitatory at muscle; varied in brain and autonomic system | Neuromuscular junction; myasthenia gravis; botulinum toxin |
| Glutamate | Main excitatory transmitter in brain and cord | Learning and plasticity; excess release damages neurons after stroke |
| GABA | Main inhibitory transmitter in the brain | Baclofen acts on GABA-B receptors to reduce spasticity |
| Glycine | Inhibitory transmitter in the spinal cord | Spinal inhibition; tetanus toxin blocks its release, causing rigidity and spasms |
| Dopamine | Modulates movement, motivation and reward | Loss from the basal ganglia causes Parkinson’s disease |
| Noradrenaline | Sympathetic transmitter; arousal | Heart rate and blood pressure responses to exercise |
| Serotonin | Mood, sleep, pain modulation | Descending control of pain |
The neuromuscular junction is the synapse between a motor neuron and a skeletal muscle fibre. Each fibre normally has one junction, near its middle.
Figure 3 · The neuromuscular junction
Acetylcholine released from the terminal binds nicotinic receptors clustered on the crests of the junctional folds. These receptors are ion channels; their opening produces a large depolarisation, the end-plate potential. Acetylcholinesterase in the cleft breaks down acetylcholine within milliseconds, so each impulse produces one brief signal.
Figure 4 · Quanta and the safety margin
Unlike a central synapse, the neuromuscular junction does not add up small inputs. One nerve impulse normally releases enough acetylcholine to produce an end-plate potential far above the muscle fibre’s threshold. This safety margin means every motor nerve impulse fires its muscle fibres, one for one.
When the margin shrinks, some fibres fail to fire, especially with repeated use as release declines slightly with each impulse. The result is weakness that worsens with effort, the hallmark of myasthenia gravis [2].
| Condition or drug | What it does | Clinical picture |
|---|---|---|
| Myasthenia gravis | Antibodies against acetylcholine receptors or associated proteins reduce the end-plate potential [2] | Fatigable weakness: drooping eyelids, double vision, swallowing and limb weakness, worse with effort |
| Lambert–Eaton syndrome | Antibodies against presynaptic calcium channels reduce release | Proximal limb weakness that may briefly improve with repeated effort; often linked to cancer |
| Botulinum toxin | Blocks acetylcholine release from the terminal | Used therapeutically to reduce focal spasticity and dystonia; effect wears off over months |
| Anticholinesterases (for example pyridostigmine) | Slow the breakdown of acetylcholine | Used to treat myasthenia gravis |
| Organophosphate poisoning | Irreversibly blocks acetylcholinesterase | Excess acetylcholine: weakness, secretions, breathing failure |
| Neuromuscular blocking drugs | Block the receptors | Used in anaesthesia and intensive care |
Exercise was long discouraged in myasthenia gravis. A 2026 systematic review of eight controlled studies found that aerobic, resistance, combined and respiratory muscle training were well tolerated in clinically stable patients. There was no evidence of sustained worsening, and functional capacity and strength improved [3]. Programmes should be individual and guided by symptoms [3].
Synapses are not fixed. In 1973 Bliss and Lømo stimulated a pathway in the rabbit hippocampus at high frequency for a few seconds. Transmission across those synapses stayed stronger for hours afterwards [4]. This long-term potentiation is now regarded as a cellular basis of learning and memory.
The same capacity for use-dependent change underlies recovery after brain injury. Kleim and Jones drew together ten principles of experience-dependent plasticity from neuroscience research and set out their relevance to rehabilitation [5].
| Principle | What it means in practice |
|---|---|
| Use it or lose it | Functions not used deteriorate |
| Use it and improve it | Training a function can enhance it |
| Specificity | What is practised is what improves |
| Repetition matters | Plasticity needs enough repetitions |
| Intensity matters | Sufficient training intensity is required |
| Time matters | Different changes happen at different times after injury |
| Salience matters | The training must matter to the person |
| Age matters | Plasticity occurs more readily in younger brains |
| Transference | Plasticity from one training can help related skills |
| Interference | Plasticity in one direction can hinder learning another, such as compensatory habits |
The principles are listed as Kleim and Jones described them [5]. They are drawn largely from animal research, and how best to apply each in human rehabilitation is still being studied [5].
| Observation | Possible synaptic basis | Action |
|---|---|---|
| Weakness that worsens with repetition and recovers with rest | Neuromuscular transmission failure | Report; test sustained up-gaze or repeated shoulder abduction |
| New breathlessness or weak cough in known myasthenia | Respiratory muscle involvement | Treat as urgent; seek medical review |
| Reduced tone weeks after botulinum injection | Blocked release in injected muscles | Intensify stretching and active training |
| Plateau in practice-based progress | Dose, specificity or salience may be too low | Review repetitions, task specificity and goals [5] |
Practical skill · screening for fatigability
Ask the patient to hold the arms out to the side at shoulder height for up to two minutes, or to look upward without blinking for a minute. Arms that drift down or eyelids that droop progressively suggest fatigable weakness. Record the time to failure so that you can compare later sessions.
Describe neuromuscular transmission. Add a note on myasthenia gravis.
Exercise is often taught as something to restrict in myasthenia gravis, and synapses are taught as fixed relay stations.
Controlled studies now suggest structured exercise is safe and helpful in clinically stable myasthenia gravis, though the trials are small and further research is needed [3].
Synaptic strength changes with use, and principles drawn from that research give rehabilitation a rationale for dose, specificity and meaning [4, 5].
Know the classic sequence of transmission for the exam. In practice, remember that synapses are where much of rehabilitation acts, and that the dose of practice matters.
10 questions on this page. Tap one to see the answer and the reasoning.
Answer: (B) Voltage-gated calcium entry triggers vesicle fusion; the packets released were first detected by Fatt and Katz [1].
Answer: (B) They described spontaneous subthreshold miniature potentials at motor nerve endings [1].
Answer: (B) The end-plate potential normally exceeds threshold by a wide margin; loss of that margin causes fatigable weakness [2].
Answer: (B) Gilhus describes autoantibodies to the acetylcholine receptor or associated proteins at the end plate [2].
Answer: (B) Fatigable weakness, often of eye, bulbar and limb muscles, is the hallmark [2].
Answer: (B) A 2026 systematic review found no evidence of sustained exacerbation and improvements in function and strength [3].
Answer: (B) Bliss and Lømo showed that brief high-frequency stimulation produced hours of increased synaptic transmission [4].
Answer: (B) Kleim and Jones list specificity among ten principles relevant to rehabilitation [5].
Answer: (B) Repetition, intensity, timing and salience are among the principles they describe [5].
Answer: (B) Fluctuating, fatigable ocular weakness is typical of myasthenia gravis [2].
Key takeaways
| Source | Why it earns its place |
|---|---|
| Kandel ER et al. — Principles of Neural Science | Detailed account of synaptic transmission and plasticity |
| Gilhus NE — New England Journal of Medicine, 2016 | Clear clinical review of myasthenia gravis [2] |
| Kleim JA, Jones TA — JSLHR, 2008 | The ten principles, explained for clinicians [5] |
| Hall JE, Hall ME — Guyton and Hall Textbook of Medical Physiology | Standard account of the neuromuscular junction |
Reviewed by the Physiotherapist India Team. · Human Physiology contents