L7 Nervous System Neurons to networks

Overview

This lecture builds a picture of the nervous system from the single neuron up to functioning networks. It starts with neuronal and non-neuronal (glial) cell types and basic terminology, then works through the electrical basis of signalling — resting membrane potential, graded potentials, and the action potential — and how action potentials propagate along axons. It then turns to chemical synaptic transmission, including the historical Otago work that established the chemical hypothesis, the clinical relevance of drug targets at synapses, and synaptic plasticity (LTP/LTD). Finally it shows how single-neuron integration (convergence, divergence, summation) scales up into networks, and what goes wrong when network-level excitation/inhibition balance fails (e.g. epilepsy).

Neuronal structure

A neuron has:

• Dendrites and cell body — receive synapses; generate local potentials (EPSP, IPSP)
• Initial segment (axon hillock) — integrates local potentials and generates the action potential
• Axon, with terminals — carries the signal and makes synapses onto the next cell

There are roughly 100,000,000,000 (100 billion) neurons in the brain, and an estimated $10^{14}$–$10^{15}$ synapses.

Non-neuronal structures and glia

• Ependyma — regulates transfer of substances between brain and cerebrospinal fluid
• Meninges — dura, arachnoid, pia

Glia:

• Microglia — phagocytose dead tissue and debris; immune response
• Astrocytes — 20–50% of the volume of most brain areas
  • Regulate flow of small molecules/ions between blood and neurons (blood–brain barrier)
  • Structural scaffold
  • Surround nodes of Ranvier; regulate extracellular fluid [K+]
  • Ensheath synapses, dendrites and neuronal cell bodies — metabolise and release neurotransmitters
  • Connect to one another via gap junctions, forming a syncytium
• Oligodendrocytes — form myelin in the CNS

The neurovascular unit (ependyma, microglia, astrocyte end-feet, oligodendrocytes, pia) physically links capillaries, neurons, and the CSF/ventricle boundary.

Glia are a source of many brain tumours; astrocytoma is the most common. Glial transmitter release and syncytial ("quadripartite synapse") function are an active area of research with growing relevance to treatments of brain disorders.

Two modes of glial involvement in transmitter signalling: short-distance communication at the quadripartite synapse (glia flank the pre- and postsynaptic elements, taking up transmitter and K+), and long-distance communication where glial processes act as diffusion barriers (volume fraction, tortuosity, uptake) shaping how far transmitter spreads outside the synapse.

Terminology

• CNS = brain + spinal cord
• Afferent = “incoming” (Latin, “bringing towards”); efferent = “outgoing” (Latin, “carrying out”)
• Relative synaptic position: if A → B → C, B is postsynaptic to A and presynaptic to C (the same neuron can be both, depending on which neighbour is referenced)
• White matter terms: tract, funiculus (rope), fascicle (bundle), lemniscus (ribbon), commissure (joining), pathway

Neurons concerned with a given function tend to group together in specific cortical regions and subcortical nuclei, connected via long white-matter projection pathways. Because of this clustering, damage to a specific region produces a specific syndrome.

Clinical point: a cortical stroke affecting language areas produces a language-specific syndrome, because the neurons for that function are localised.

Resting membrane potential (RMP)

Ionic basis (four steps):

1. Concentration gradients for Na+ and K+ are set up by ion pumps (Na+/K+ pump)
2. Differential resting permeability: K+ permeability > Na+ permeability (Na+ permeability ≈ 0)
3. K+ diffuses out down its concentration gradient, creating an electrostatic gradient
4. When the concentration and electrostatic gradients balance, this equilibrium is $E_K$ ≈ RMP

How signals arise from RMP:

• K+ moving out, or increased K+ permeability → membrane becomes more negative (hyperpolarise)
• Na+ moving in, or increased Na+ permeability → membrane becomes less negative or even positive (depolarise)
• Transient variations in RMP are the signals: graded (local/passive) potentials and action potentials

Graded potentials

Properties:

• Small changes in membrane potential, confined to a small region of the membrane
• Decremental: die out within 1–2 mm of origin
• Produced by a specific change in the cell’s environment acting on a specialised receptor/channel region of membrane
• Called “graded” because the magnitude of the potential change varies (is graded) with stimulus size
• May depolarise or hyperpolarise the membrane
• Can summate — temporally or spatially

Named according to location/function:

• Receptor potential — at peripheral endings of afferent neurons
• Synaptic potential — in the postsynaptic neuron, in response to neurotransmitter released from the presynaptic terminal

Ionic basis:

1. Stimulus opens mechanically or chemically gated ion channels
2. Ions flow along their electrochemical gradients
3. Membrane potential changes: the size of the potential change is proportional to the size of the stimulus, and the change spreads decrementally with distance

What graded potentials are for: they allow integration of multiple inputs.

Action potentials

Definition: rapid, large alterations in membrane potential — the membrane may change by around 100 mV (from about –70 mV to +30 mV), then repolarises back to RMP.

Ionic basis (six steps):

1. Local (graded) potential produces some Na+ entry
2. Threshold is reached
3. Rapid opening of voltage-gated Na+ channels; more Na+ enters
4. Membrane potential approaches the sodium equilibrium potential
5. Slower opening of voltage-gated K+ channels allows K+ exit; Na+ channels close
6. Membrane potential approaches the potassium equilibrium potential (producing the after-hyperpolarisation before returning to RMP)

Underlying this: Na+ permeability (PNa) rises fast to an earlier, lower peak driving the rising phase (steps 1–4); K+ permeability (PK) rises more slowly to a higher, longer-lasting peak, driving repolarisation and after-hyperpolarisation (steps 5–6).

What the action potential is for:

• Converts analog synaptic input into a digital “1” output
• “Regenerative,” so it delivers this output over long distances without losing signal strength

Propagation of the action potential

• Continuous conduction: the AP process occurs in every bit of membrane; reliable, but the spread of current along the axon from each AP is fast but limited in extent, and each AP takes time — so conduction is slow.
• Saltatory conduction: myelin reduces current loss, so current from an AP spreads further and conduction is faster; fewer APs are generated (regenerated only at nodes), so less energy is used. Loss of myelin causes conduction failure.

Loss of myelin leads to conduction failure. Relevant clinically to trauma and to demyelinating diseases: multiple sclerosis and Guillain-Barré Syndrome (no channels exist under the myelin itself, so continuity depends on the nodes).

Clinical relevance of the action potential: drugs acting at channels are used to control action potential generation, e.g. local anaesthetics and anti-epileptics.

Synapses and synaptic transmission

Definition: a synapse is an anatomically specialised junction between two neurons at which electrical activity in one neuron (presynaptic) influences electrical activity in a second neuron (postsynaptic).

• Active synapses produce a brief, graded potential that may be excitatory or inhibitory.
• The overall number and types of inputs onto a postsynaptic neuron determine whether it fires an action potential.

Mechanism and transmitter classes (from the synaptic transmission diagram):

• On depolarisation of the presynaptic terminal, Ca2+ enters via Ca2+ channels, triggering release of neurotransmitter.
• Small-molecule neurotransmitters (e.g. formed from acetyl-CoA + choline) are concentrated into small vesicles by a vesicle transporter, released into the cleft, and act on ionotropic and G-protein-coupled receptors on the postsynaptic cell. They are cleared by enzymes (e.g. acetylcholinesterase) and by reuptake transporters.
• Neuropeptides are packaged in large, electron-dense vesicles and, once released, diffuse further in the extracellular space to act on synaptic and extrasynaptic G-protein-coupled receptors, activating a variety of enzymes.
• Gaseous transmitters (e.g. nitric oxide, NO): arginine is converted via NO synthase (through citrulline) to NO, which is not packaged in vesicles but diffuses directly out of the cell of origin and can act within that cell or in distant cells.

Otago and the discovery of chemical neurotransmission

Sir John “Jack” Carew Eccles (Head of Physiology, University of Otago, 1944–1952) initially championed an electrical hypothesis of synaptic transmission and central inhibition (1945 and 1947 papers, published from Otago). In a 1952 paper (Brock, Coombs & Eccles, using intracellular recording from motoneurones), the group concluded that an electrical explanation of inhibitory synaptic transmission was excluded, and that inhibitory synaptic action is instead mediated by a specific transmitter substance released from inhibitory synaptic knobs, causing increased polarisation of the motoneurone membrane — and by extension that excitatory synaptic action is also mediated by a chemical transmitter. Eccles shared the 1963 Nobel Prize in Physiology or Medicine with Alan Hodgkin and Andrew Huxley “for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane.”

Flag from transcript: a further line of quoted text from the 1952 paper excerpt is cut off/illegible at the bottom edge of the slide image and could not be transcribed.

Why the chemical nature of transmission matters

Because transmission is chemical, synapses are sites of disease and toxin action, and targets for drugs at several points:

• Transmitter synthesis
• Transmitter release
• Receptors (agonists, antagonists)
• Signalling pathways

(Illustrated on the slide by the dopaminergic synapse: synthesis, vesicular packaging via VMAT, exocytosis, DAT reuptake, autoreceptor D2, MAO/COMT breakdown, and postsynaptic D1/D2 receptors signalling via G-proteins/cAMP/PKA to downstream targets.)

Synaptic plasticity

Sustained or special activation increases receptor number and responsiveness. Synaptic plasticity is a change in synaptic efficacy — long-term potentiation (LTP) and long-term depression (LTD) — and can involve:

• Transmitter synthesis
• Transmitter release
• Receptor number
• Signalling pathways
• Synaptic morphology

Mechanism shown for LTP:

1. NMDA receptor opens
2. Ca2+ enters, activating CaM-KII
3. Linking proteins attach to CaM-KII
4. AMPA receptors are delivered to the membrane in vesicles
5. Additional AMPA receptors are inserted into the membrane

This is accompanied by synaptic morphology change: before LTP there are fewer docked vesicles at a small active zone; after LTP there are more vesicles and an enlarged, perforated active zone at the dendritic spine.

Significance: this enables long-term storage of information (memory), and is also implicated in pathology such as chronic pain.

Networks: convergence, divergence, and integration

Two basic connectivity motifs combine to build neural networks:

• Convergence — many upstream neurons’ axons synapse onto a single downstream neuron
• Divergence — one neuron’s axon branches to synapse onto multiple downstream neurons

Convergence and integration of inputs

Every neuron receives inputs from many (tens of thousands) of synapses, including both excitatory and inhibitory inputs. Temporal and spatial summation of these inputs produces logic-like functions:

1. Low-frequency activity: two EPSPs separated in time do not summate.
2. High-frequency activity at one input: EPSP 2 adds to EPSP 1 — temporal summation.
3. A second input terminating elsewhere on the neuron: when both inputs are active together, their EPSPs spread to the axon initial segment and add — spatial summation.
4. Combined inputs summate enough to cross threshold and trigger a response — an “AND” function.
5. An inhibitory input can “veto” excitation even when excitatory inputs are present — a “NOT” function.

Divergence

An axon branches to reach multiple targets, enabling:

• Broadcast signalling (e.g. reward, danger)
• Parallel processing of the same information
• Monitoring of self-action via efference copy (a copy of a motor command sent to other circuits)

Networks and dysfunction

Networks are built from neural integration (convergence), information sharing (divergence), and looping (recurrent connections). All brain functions — perception, behaviour, emotions, thoughts, memory, consciousness — rely on network activity, illustrated by the dense interconnected wiring of cortical/association areas.

Network function depends on a balance between excitation (glutamate/aspartate) and inhibition (GABA).

When global network function goes wrong (excitation/inhibition balance disrupted), this manifests as epilepsy, coma, brain death, or chronic regional pain syndrome.

Self-test

1. Name the three main functional regions of a neuron involved in receiving, integrating, and generating a signal, and state what each one does.
2. List the three glial cell types described and give one function of each.
3. Distinguish afferent from efferent, and explain the presynaptic/postsynaptic relationship using a chain of three neurons A→B→C.
4. Why does functional clustering of neurons into specific cortical regions and subcortical nuclei explain why a stroke produces a specific syndrome?
5. Describe the four steps that establish the resting membrane potential.
6. Explain why increasing K+ permeability hyperpolarises the membrane while increasing Na+ permeability depolarises it.
7. List the defining properties of a graded potential (four properties).
8. Distinguish a receptor potential from a synaptic potential.
9. Describe the six-step ionic mechanism of the action potential.
10. What is the functional significance of the “regenerative” property of the action potential?
11. Distinguish continuous from saltatory conduction, and explain why myelin loss causes conduction failure.
12. A patient is given a local anaesthetic before a dental procedure. What is the general mechanism by which this class of drug prevents pain signalling?
13. Describe the mechanism of chemical synaptic transmission from presynaptic depolarisation to receptor binding.
14. Distinguish the release and action of small-molecule neurotransmitters, neuropeptides, and gaseous transmitters (e.g. NO).
15. Explain why Eccles’s 1952 intracellular recording result overturned the earlier electrical hypothesis of inhibition.
16. List the points in chemical synaptic transmission that can be targeted by drugs or disrupted by disease.
17. Describe the molecular steps by which LTP increases synaptic responsiveness, and the associated change in synaptic morphology.
18. Distinguish convergence from divergence, and give one functional consequence of each.
19. A neuron receives two low-frequency excitatory inputs from the same synapse, then the same synapse fires at high frequency. Explain the difference in outcome (temporal summation) and predict what would happen if a third, inhibitory input fired simultaneously with two excitatory inputs.
20. Integrative: trace the pathway from a stimulus opening a receptor channel through to an action potential propagating along a myelinated axon and triggering neurotransmitter release, naming the key ionic/mechanistic step at each stage.
21. What does the excitation/inhibition balance in a network refer to, and what are the consequences of its disruption?

Answers

Reveal answers

1. Dendrites/cell body (receive synapses, generate local potentials — EPSP/IPSP); initial segment/axon hillock (integrates local potentials, generates the action potential); axon and terminals (carry the signal, form synapses onto the next cell).
2. Microglia — phagocytose dead tissue/debris (immune response); astrocytes — e.g. regulate the blood-brain barrier and ECF K+ at nodes of Ranvier, form a syncytium; oligodendrocytes — form myelin in the CNS.
3. Afferent = incoming (towards the CNS); efferent = outgoing (away from the CNS). In A→B→C, B is postsynaptic relative to A and presynaptic relative to C — the same neuron can hold both roles depending on which neighbour is being referenced.
4. Because neurons serving a given function cluster together in specific cortical regions/subcortical nuclei, damage confined to one such region knocks out that specific function (e.g. language areas), producing a recognisable syndrome rather than a diffuse deficit.
5. (1) Ion pumps set up Na+/K+ concentration gradients; (2) resting permeability favours K+ over Na+ (Na+ ≈ 0); (3) K+ diffuses out down its concentration gradient, creating an electrostatic gradient; (4) the concentration and electrostatic gradients balance at Ek, which approximates RMP.
6. K+ efflux/permeability moves the membrane potential toward Ek, which is negative, making the inside more negative (hyperpolarisation); Na+ influx/permeability moves the potential toward the (positive) Na+ equilibrium potential, making the inside less negative or positive (depolarisation).
7. Small, confined to a small region of membrane; decremental (die out within 1–2 mm); triggered by a stimulus acting on a specialised receptor/channel region; graded in magnitude (proportional to stimulus size); may depolarise or hyperpolarise; can summate temporally or spatially.
8. A receptor potential arises at the peripheral endings of afferent neurons; a synaptic potential arises in a postsynaptic neuron in response to neurotransmitter released from a presynaptic terminal.
9. (1) Local potential with some Na+ entry; (2) threshold reached; (3) rapid opening of voltage-gated Na+ channels, more Na+ entry; (4) membrane potential approaches the Na+ equilibrium potential; (5) slower opening of voltage-gated K+ channels, K+ exits, Na+ channels close; (6) membrane potential approaches the K+ equilibrium potential.
10. Because the action potential regenerates itself along the axon rather than decaying, it can carry a full-strength signal over long distances without loss — unlike a graded potential.
11. Continuous conduction activates every segment of membrane in sequence (reliable but slow, since current spread from each AP is limited and each AP takes time); saltatory conduction “jumps” between nodes of Ranvier because myelin reduces current loss, so current spreads further and conduction is faster with fewer regenerated APs. Myelin loss causes conduction failure because there are no channels under the myelin, so continuity depends on the (now-disrupted) node-to-node jumps.
12. Local anaesthetics act at channels (as noted for drugs generally) to control/block action potential generation, preventing the signal from being generated or propagated.
13. Depolarisation of the presynaptic terminal opens Ca2+ channels; Ca2+ enters and triggers release of neurotransmitter from vesicles into the synaptic cleft; the transmitter diffuses across the cleft and binds ionotropic or G-protein-coupled receptors on the postsynaptic cell.
14. Small-molecule transmitters are packaged in small vesicles, released by Ca2+-triggered exocytosis, act locally on ionotropic/GPCRs, and are cleared by enzymes (e.g. acetylcholinesterase) or reuptake. Neuropeptides are packaged in large dense-core vesicles and diffuse further to act on synaptic/extrasynaptic GPCRs. Gaseous transmitters (e.g. NO) are synthesised on demand (arginine → citrulline + NO via NO synthase), are not vesicle-packaged, and diffuse directly out of the cell to act intracellularly or in distant cells.
15. Using intracellular recording from motoneurones, Eccles and colleagues showed the electrical explanation of inhibitory synaptic transmission was excluded and that inhibition instead correlated with release of a specific transmitter substance causing increased polarisation — evidence incompatible with a purely electrical hypothesis.
16. Transmitter synthesis, transmitter release, receptors (agonists/antagonists), and signalling pathways.
17. NMDA receptor opens → Ca2+ enters and activates CaM-KII → linking proteins attach to CaM-KII → AMPA receptors are delivered to the membrane in vesicles → additional AMPA receptors are inserted into the membrane. Synaptic morphology changes from a small active zone with few docked vesicles to an enlarged, perforated active zone with more vesicles.
18. Convergence: many neurons synapse onto one, enabling integration/summation into logic-like output. Divergence: one neuron’s axon branches to many targets, enabling broadcast signalling, parallel processing, and efference copy.
19. Low-frequency inputs each decay before the next arrives, so there is no summation; high-frequency firing at the same synapse causes each new EPSP to add to the residual depolarisation from the previous one (temporal summation), raising the peak. If an inhibitory input fires simultaneously with the two excitatory inputs, it can hyperpolarise the membrane and veto (prevent) the excitatory inputs from reaching threshold — a “NOT” function.
20. Stimulus opens a mechanically/chemically gated channel → ions flow down their electrochemical gradient, producing a graded potential proportional to stimulus size → if summation at the initial segment reaches threshold, voltage-gated Na+ channels open rapidly (depolarisation) → voltage-gated K+ channels open more slowly, repolarising and after-hyperpolarising the membrane → the resulting action potential propagates saltatorily along the myelinated axon (jumping node to node) → on reaching the terminal, depolarisation opens Ca2+ channels → Ca2+ entry triggers neurotransmitter release into the synaptic cleft.
21. It refers to the balance between excitatory (glutamate/aspartate) and inhibitory (GABA) drive across a network. Disruption of this balance underlies dysfunctions such as epilepsy, coma, brain death, and chronic regional pain syndrome.