Introduction to Neurones, Synapses and Drug Action
Welcome to one of the most exciting topics in Biology! Your nervous system allows you to sense the environment, think, move, and respond in fractions of a second. Whether you pull your hand away from a hot stove or read these study notes, your body is using specialised cells called neurones that conduct electrical impulses and communicate via chemical signals across microscopic gaps known as synapses.
In this chapter, we will break down the structure of different neurones, trace how electrical impulses are generated and conducted, explore chemical transmission across synapses, and discover how specific drugs and toxins alter nerve transmission.
1. Types of Neurones and the Reflex Arc
The nervous system consists of two major structural divisions: the central nervous system (CNS), which comprises the brain and spinal cord, and the peripheral nervous system (PNS), which includes all the nerves connecting the CNS to the rest of the body.
Three Main Classes of Neurones
Neurones are specialised cells adapted for the transmission of electrical impulses. You need to know the structure and function of three types:
1. Sensory Neurones:
These carry impulses from receptors (which detect stimuli) into the CNS. They typically have a long dendron carrying impulses toward the cell body and a shorter axon carrying impulses away from the cell body into the spinal cord. The cell body is located outside the CNS in the dorsal root ganglion.
2. Relay Neurones (Interneurones):
These are located entirely within the CNS (spinal cord or brain). They connect sensory neurones to motor neurones (or connect to other relay neurones). They typically have short, heavily branching dendrites and short axons.
3. Motor Neurones:
These transmit impulses from the CNS to effectors (muscles or glands) to bring about a response. They have a cell body located in the grey matter of the spinal cord, numerous short dendrites extending from the cell body, and a long axon terminating at an effector organ.
The Structure of a Myelinated Neurone
Many vertebrate neurones are insulated by a fatty layer called a myelin sheath:
• Cell body (soma): Contains the nucleus, mitochondria, rough endoplasmic reticulum, and other organelles needed for protein synthesis.
• Dendrites: Thin, branched extensions that receive impulses from other neurones or receptors and conduct them toward the cell body.
• Axon: A long, single fibre that conducts nerve impulses away from the cell body.
• Schwann cells: Specialised support cells that wrap around the axon multiple times to lay down layers of lipid-rich membrane forming the myelin sheath.
• Nodes of Ranvier: Uninsulated gaps in the myelin sheath occurring at regular intervals (approximately every \(1\text{ mm}\)) along the axon where the axon membrane is exposed.
The Spinal Reflex Arc
A reflex is a rapid, involuntary, and automatic response to a stimulus that does not require conscious thought from the brain. It serves a vital protective role.
The neural pathway underlying a reflex is called a reflex arc. The sequence of transmission is:
Stimulus \(\implies\) Receptor (detects stimulus) \(\implies\) Sensory Neurone \(\implies\) Relay Neurone (in spinal cord grey matter) \(\implies\) Motor Neurone \(\implies\) Effector (muscle contracts or gland secretes) \(\implies\) Response.
Example: The pupil reflex involves the contraction and dilation of the pupil to protect the retina from excessive light levels. In bright light, circular muscles contract and radial muscles relax to constrict the pupil; in dim light, radial muscles contract and circular muscles relax to dilate the pupil. (For more details on retinal receptors, see the chapter on Receptors, the Brain and Medical Imaging).
Key Takeaway: Sensory neurones carry impulses to the CNS, relay neurones process within the CNS, and motor neurones conduct impulses to effectors. Myelin sheaths are produced by Schwann cells, interrupted by nodes of Ranvier.
2. The Nerve Impulse: Action Potentials and Conduction
A nerve impulse is not a flow of electrons down a wire. It is a temporary, rapid reversal of electrical potential across the axon membrane caused by the regulated movement of sodium ions (\(\text{Na}^+\)) and potassium ions (\(\text{K}^+\)) down electrochemical gradients.
The Resting Potential (\(-70\text{ mV}\))
When a neurone is not conducting an impulse, the inside of the axon is negatively charged relative to the outside. This polarised state is known as the resting potential, and in humans, it sits at approximately \(-70\text{ mV}\).
The resting potential is established and maintained by three key mechanisms:
1. The Sodium-Potassium Pump (\(\text{Na}^+/\text{K}^+\) ATPase):
This carrier protein actively transports \(3\text{ Na}^+\) ions out of the axon for every \(2\text{ K}^+\) ions pumped in, using energy from the hydrolysis of \(\text{ATP}\). This establishes chemical concentration gradients: high \(\text{Na}^+\) concentration outside, high \(\text{K}^+\) concentration inside.
2. Differential Membrane Permeability:
The resting membrane contains permanently open non-voltage-gated \(\text{K}^+\) "leak" channels, but very few open \(\text{Na}^+\) leak channels. Therefore, the membrane is much more permeable to \(\text{K}^+\) than to \(\text{Na}^+\).
3. Potassium Ion Diffusion:
\(\text{K}^+\) ions diffuse out of the axon down their concentration gradient through the leak channels. As positive charge leaves the cell, the interior becomes negative relative to the exterior. Eventually, an electrochemical equilibrium is reached where the electrical gradient pulling \(\text{K}^+\) back in balances the chemical gradient driving \(\text{K}^+\) out.
The Action Potential
When an adequate stimulus arrives at the membrane, the resting potential temporarily changes into an action potential. This happens in distinct phases:
Phase 1: Depolarisation
• A stimulus causes temporary opening of some voltage-gated \(\text{Na}^+\) channels.
• \(\text{Na}^+\) ions enter the axon down their electrochemical gradient.
• If the potential reaches the threshold potential (around \(-55\text{ mV}\)), voltage-gated \(\text{Na}^+\) channels open rapidly en masse (a positive feedback mechanism).
• \(\text{Na}^+\) floods in, causing rapid reversal of membrane polarity to approximately \(+30\text{ mV}\) to \(+40\text{ mV}\).
Phase 2: Repolarisation
• At the peak of the action potential (around \(+30\text{ mV}\)), the voltage-gated \(\text{Na}^+\) channels close and become temporarily inactivated.
• Voltage-gated \(\text{K}^+\) channels open in response to depolarisation.
• \(\text{K}^+\) ions diffuse rapidly out of the axon down their electrochemical gradient, restoring the negative charge inside the axon.
Phase 3: Hyperpolarisation and the Refractory Period
• Voltage-gated \(\text{K}^+\) channels are slow to close, allowing an excess of \(\text{K}^+\) ions to diffuse out.
• The membrane potential briefly drops below the resting value to around \(-80\text{ mV}\). This state is called hyperpolarisation.
• The voltage-gated \(\text{K}^+\) channels close, and resting potential (\(-70\text{ mV}\)) is restored by the constant action of the \(\text{Na}^+/\text{K}^+\) pump and \(\text{K}^+\) leak channels.
• During this time, the membrane is in a refractory period where another action potential cannot be generated immediately. This ensures that action potentials are discrete, separate events and guarantees that impulses travel in only one direction.
The "All-or-Nothing" Principle: An action potential either occurs completely or does not occur at all. As long as the stimulus exceeds the threshold value, an action potential of constant size is triggered. A stronger stimulus does not produce a larger action potential; instead, it generates a higher frequency of action potentials.
Conduction Along the Axon and Saltatory Conduction
In an unmyelinated axon, influx of \(\text{Na}^+\) creates local electrical circuits between the depolarised region and the adjacent resting region. This depolarises the adjacent region to threshold, triggering an action potential there. This wave of depolarisation moves steadily along the whole length of the axon, which is relatively slow (e.g. \(1\text{ to }2\text{ m s}^{-1}\)).
In a myelinated axon:
• Myelin is an electrical insulator that prevents movement of ions across the axon membrane.
• Voltage-gated \(\text{Na}^+\) and \(\text{K}^+\) channels are concentrated almost exclusively at the nodes of Ranvier.
• Local circuits set up between adjacent nodes, causing the action potential to "jump" from one node of Ranvier to the next.
• This process is called saltatory conduction (from the Latin saltare, to leap).
• Saltatory conduction greatly increases the speed of transmission (up to \(100\text{ to }120\text{ m s}^{-1}\)) and conserves energy because the \(\text{Na}^+/\text{K}^+\) pump only needs to re-establish ion gradients at the nodes, using less \(\text{ATP}\).
Common Mistake to Avoid: Never say that "sodium and potassium trade places completely." Only a tiny fraction of the total intracellular and extracellular ions actually move across the membrane during an action potential, but this is enough to dramatically reverse the voltage across the membrane.
Key Takeaway: Resting potential (\(-70\text{ mV}\)) depends on the \(\text{Na}^+/\text{K}^+\) pump and \(\text{K}^+\) leak channels. Depolarisation is driven by \(\text{Na}^+\) influx through voltage-gated channels; repolarisation is driven by \(\text{K}^+\) efflux. Myelination enables rapid saltatory conduction from node to node.
3. Synaptic Transmission
A synapse is a junction between two neurones (or between a motor neurone and an effector). The tiny gap separating them is the synaptic cleft (about \(20\text{ nm}\) wide). Because an electrical action potential cannot cross this physical gap, transmission depends on chemical messengers called neurotransmitters.
Structure of a Cholinergic Synapse
A cholinergic synapse uses the neurotransmitter acetylcholine (ACh). The junction consists of:
• Presynaptic knob: The swollen terminal of the incoming axon, containing mitochondria, synaptic vesicles filled with acetylcholine, and voltage-gated calcium ion (\(\text{Ca}^{2+}\)) channels in its membrane.
• Synaptic cleft: The fluid-filled gap.
• Postsynaptic membrane: The membrane of the receiving cell, containing specific complementary receptor proteins associated with ligand-gated ion channels.
Step-by-Step Mechanism of Synaptic Transmission
1. Arrival of the action potential:
The action potential arrives at the presynaptic knob, depolarising the presynaptic membrane.
2. Calcium influx:
Depolarisation causes voltage-gated \(\text{Ca}^{2+}\) channels in the presynaptic membrane to open. Calcium ions (\(\text{Ca}^{2+}\)) diffuse rapidly into the presynaptic knob down their electrochemical gradient.
3. Vesicle fusion (Exocytosis):
The influx of \(\text{Ca}^{2+}\) causes synaptic vesicles containing acetylcholine to move toward and fuse with the presynaptic membrane, releasing acetylcholine into the synaptic cleft by exocytosis.
4. Diffusion across the cleft:
Acetylcholine diffuses across the narrow synaptic cleft down its concentration gradient.
5. Binding to postsynaptic receptors:
Acetylcholine molecules bind reversibly to complementary binding sites on receptor proteins in the postsynaptic membrane.
6. Postsynaptic depolarisation:
Binding of ACh causes ligand-gated sodium ion (\(\text{Na}^+\)) channels to open. \(\text{Na}^+\) ions diffuse into the postsynaptic cell, causing depolarisation (an excitatory postsynaptic potential). If depolarisation reaches threshold, a new action potential is triggered along the postsynaptic neurone.
7. Breakdown and recycling of acetylcholine:
The enzyme acetylcholinesterase, situated on the postsynaptic membrane, rapidly hydrolyses acetylcholine into acetate (ethanoic acid) and choline. This prevents continuous, uncontrolled stimulation of the postsynaptic receptor.
Choline is taken back up into the presynaptic knob via active transport. Mitochondria provide \(\text{ATP}\) to recombine choline with acetyl-CoA to regenerate acetylcholine, which is repackaged into vesicles.
Key Roles of Synapses
• Unidirectionality: Synaptic vesicles containing neurotransmitters are only present in the presynaptic knob, and specific complementary receptors are only present on the postsynaptic membrane. Impulses can therefore only pass in one direction.
• Integration and Summation: Individual low-frequency impulses may release insufficient neurotransmitter to reach threshold. Multiple impulses arriving close together in time (temporal summation) or from multiple presynaptic neurones converging on one postsynaptic neurone (spatial summation) combine to reach threshold and trigger an action potential.
• Filtering out low-level stimuli: Prevents sensory overload from background noise or minor fluctuations in the environment.
Key Takeaway: Synaptic transmission relies on \(\text{Ca}^{2+}\) entry triggering exocytosis of acetylcholine, diffusion across the cleft, binding to ligand-gated receptors, and rapid enzymatic breakdown by acetylcholinesterase to maintain unidirectional communication.
4. Drug Action on the Nervous System
Many chemicals, medical drugs, and toxins alter nervous system function by interfering with action potentials or synaptic transmission. The Pearson Edexcel IAL syllabus requires you to understand the exact mechanisms of five named substances:
1. Nicotine
• Mechanism: Nicotine has a molecular shape very similar to acetylcholine. It binds to acetylcholine receptors on postsynaptic membranes (known as nicotinic receptors).
• Action: It acts as an agonist: upon binding, it opens ion channels and depolarises the postsynaptic neurone, initiating an impulse.
• Physiological effect: Nicotine is not broken down by acetylcholinesterase, leading to prolonged stimulation. In the brain, this triggers release of neurotransmitters such as dopamine, leading to increased alertness and addiction. In the autonomic nervous system, it raises heart rate and blood pressure.
2. Lidocaine
• Mechanism: Lidocaine is a synthetic chemical used as a local anaesthetic (e.g. at the dentist).
• Action: It blocks voltage-gated \(\text{Na}^+\) channels in the membranes of sensory neurones.
• Physiological effect: By blocking \(\text{Na}^+\) entry, lidocaine prevents threshold depolarisation from occurring. No action potentials can be generated or conducted along sensory axons, preventing pain impulses from reaching the central nervous system.
3. Cobra Venom Alpha Toxin (\(\alpha\)-neurotoxin)
• Mechanism: This protein toxin from cobra venom binds irreversibly to acetylcholine receptors on postsynaptic membranes, particularly at neuromuscular junctions (synapses between motor neurones and skeletal muscle fibres).
• Action: It acts as a competitive antagonist: it blocks acetylcholine from binding, but it does not open the ion channels.
• Physiological effect: Postsynaptic membranes cannot depolarise. Muscle fibres fail to receive stimulation, resulting in flaccid paralysis. Death typically occurs from asphyxiation due to paralysis of the diaphragm and intercostal muscles.
4. L-DOPA (Treatment for Parkinson's Disease)
• Context: Parkinson's disease is a neurodegenerative disorder caused by the progressive death of dopamine-secreting neurones in the brain (in the substantia nigra). Dopamine deficiency causes motor symptoms like tremors, muscle stiffness, and difficulty initiating movements.
• Mechanism: Dopamine itself cannot cross the blood-brain barrier, so administering dopamine directly is ineffective. However, L-DOPA (levodopa) is the natural biochemical precursor to dopamine, and it can cross the blood-brain barrier via specific transport proteins.
• Physiological effect: Once inside the brain, the enzyme dopa-decarboxylase converts L-DOPA into active dopamine. This restores dopamine concentrations in the synapses of the basal ganglia, substantially relieving motor symptoms.
5. MDMA (Ecstasy)
• Mechanism: MDMA alters transmission at serotonergic synapses (which use serotonin as the neurotransmitter). It binds to and reverses the action of serotonin reuptake transporter proteins in the presynaptic membrane, while also stimulating the release of serotonin from presynaptic vesicles.
• Action: This prevents serotonin from being cleared from the synaptic cleft and floods the cleft with massive concentrations of serotonin.
• Physiological effect: Prolonged activation of postsynaptic serotonin receptors leads to feelings of intense euphoria, heightened empathy, and altered sensory perception. However, prolonged use depletes the brain's serotonin stores, leading to post-drug "crashes" characterised by depression, anxiety, and altered thermoregulation (hyperthermia).
Summary Table of Named Drugs and Chemicals
Use this quick reference to distinguish their precise biological sites of action:
Nicotine:
• Site of action: Postsynaptic acetylcholine receptors.
• Mechanism: Agonist (mimics acetylcholine; stimulates receptor; not broken down by acetylcholinesterase).
• Result: Increased firing of postsynaptic neurones; releases dopamine/adrenaline.
Lidocaine:
• Site of action: Voltage-gated \(\text{Na}^+\) channels in axon membrane of sensory neurones.
• Mechanism: Blocks \(\text{Na}^+\) channel pore.
• Result: Prevents depolarisation and action potential propagation; blocks pain signals.
Cobra Venom Alpha Toxin:
• Site of action: Postsynaptic acetylcholine receptors at neuromuscular junctions.
• Mechanism: Antagonist (binds to and blocks ACh receptors irreversibly).
• Result: Prevents postsynaptic depolarisation; causes muscle paralysis.
L-DOPA:
• Site of action: Crosses blood-brain barrier into brain neurones.
• Mechanism: Converted into dopamine by dopa-decarboxylase.
• Result: Increases synaptic dopamine levels; alleviates Parkinson's disease symptoms.
MDMA:
• Site of action: Presynaptic serotonin transporter proteins and vesicles.
• Mechanism: Reverses reuptake transporters and stimulates massive release of serotonin.
• Result: Floods synaptic cleft with serotonin; causes euphoria; leads to serotonin depletion.
Key Takeaway: Drugs can act presynaptically (e.g. MDMA stimulating release/inhibiting reuptake, L-DOPA providing precursor) or postsynaptically (e.g. nicotine activating receptors, cobra venom blocking receptors), or along the axon membrane (e.g. lidocaine blocking voltage-gated \(\text{Na}^+\) channels).
Quick Review: Essential Concept Checklist
Before moving on to the next chapter, make sure you can answer each of these questions confidently:
• Can you draw and describe the pathway of a spinal reflex arc from stimulus to response?
• Why is the resting potential \(-70\text{ mV}\), and how do the \(\text{Na}^+/\text{K}^+\) pump and \(\text{K}^+\) leak channels create it?
• What happens to voltage-gated \(\text{Na}^+\) and \(\text{K}^+\) channels during depolarisation, repolarisation, and hyperpolarisation?
• How does saltatory conduction in myelinated axons differ from conduction in unmyelinated axons?
• What role do \(\text{Ca}^{2+}\) ions play in the presynaptic knob during neurotransmitter release?
• Why is acetylcholinesterase vital for proper functioning of cholinergic synapses?
• Can you state the exact molecular target and physiological effect of nicotine, lidocaine, cobra venom alpha toxin, L-DOPA, and MDMA?