2. CNS 3 Excitation in the Brain

What is essential for normal brain function & what are the main neurotransmitters involved?

• GABA: main inhibitory neurotransmitter

• Glutamate: main excitatory neurotransmitter

• Balance between them is essential for normal brain function

• Too much GABA (inhibition) → ↓ brain activity → coma (e.g. barbiturate overdose)

• Too much glutamate (excitation) → ↑ brain activity → epilepsy

• Imbalance can lead to neurological disorders

What are the main excitatory neurones in the cerebral cortex and their function?

• The cerebral cortex contains pyramidal projection neurones and interneurones.

• Pyramidal projection neurones send signals to other brain areas.

• These projection neurones form excitatory synapses on post-synaptic neurones.

• Most of these projection neurones release glutamate, the primary excitatory neurotransmitter in the brain.

How do excitatory synapses work?

• Excitatory synapses release glutamate from presynaptic terminals.

• Glutamate binds to receptors on the postsynaptic density (PSD).

• This process generates excitatory postsynaptic potentials (EPSPs) in the postsynaptic neuron.

• EPSPs are summated in dendrites to reach the threshold of ~55 mV.

• If the threshold is reached, an action potential is initiated at the axonal hillock.

What is the process at an excitatory synapse involving glutamate?

• Glutamate is stored in synaptic vesicles in the presynaptic terminal.

• When an AP arrives, vesicles fuse with the membrane (exocytosis), releasing glutamate into the synaptic cleft.

• Glutamate binds to receptors on the postsynaptic cell, causing receptor conformation change and opening ion channels.

• This leads to the influx of sodium (Na+) ions into the postsynaptic dendrite, causing a depolarization.

• Depolarization reduces the membrane potential towards more positive values, creating an excitatory postsynaptic potential (EPSP).

What is synaptic summation and how does it contribute to action potential initiation?

• Multiple EPSPs build up at the dendrite.

• If the membrane potential reaches ~-55 mV, voltage-gated Na+ channels open.

• Leads to rapid Na+ influx and depolarization, triggering an AP.

What happens in an electrophysiological experiment to monitor excitatory synaptic transmission?

• Electrodes are placed in presynaptic & postsynaptic cells

• EPSP detected in postsynaptic neuron after AP in presynaptic

• Fast synaptic transmission occurs (milliseconds)

• Multiple EPSPs occur rapidly, happening at the scale of milliseconds

What are the two types of synaptic glutamate receptors & how do they work?

• ionotropic glutamate receptors:

  • Ligand-gated ion channels

  • Glutamate binding → opens channel → Na⁺ (±K⁺) influx → EPSP

  • Quickly desensitise (close) even if glutamate remains bound

  • Fast transmission (milliseconds)

• Metabotropic glutamate receptors:

  • G-protein coupled receptors

  • Glutamate binding → activates G-proteins → intracellular signalling

  • Slower transmission (seconds to minutes)

  • No ion channel — signal is chemical → chemical

How are ionotropic & metabotropic glutamate receptors distributed in the synapse?

• Ionotropic glutamate receptors:

  • Postsynaptic: AMPA, NMDA, Kainate

  • Presynaptic: Kainate

• Metabotropic glutamate receptors:

  • Presynaptic & postsynaptic

What’s the most abundant neurotransmitter receptor in the brain?

Glutamate

What are the types & functions of ionotropic glutamate receptors?

• 3 types:

  • AMPA

  • NMDA

  • Kainate

• All allow ↑ Na⁺ influx & slight K⁺ efflux → depolarization & AP generation

• NMDA & some AMPA receptors also allow ↑ Ca²⁺ influx → further depolarization

• Differ in cation permeability & drug sensitivity

• Agonists (e.g. AMPA, NMDA, kainic acid) induce seizures in animal models

• Antagonists suppress seizures

What is each subunit of AMPA, NMDA & kainate receptors composed of?

• Large extracellular N-terminus

• Four transmembrane domains

• Large intracellular C-terminus

What are the key features of AMPA receptors in the CNS?

• Mediate most fast excitatory transmission in CNS

• Tetramers made from GluA1–4 subunits (each from a separate gene)

• Glutamate binds at extracellular loop & N-terminal domain

• C-terminal region involved in trafficking & clustering

• AMPA receptors show rapid desensitization

• GluA1, 3 & 4 ↑ Ca²⁺ permeability

• GluA2-containing receptors ↓ Ca²⁺ permeability (due to RNA editing)

• Topiramate is an anti-epileptic drug that inhibits AMPA receptors but also acts on other targets

What are the key features of NMDA receptors?

• Tetramers: 2 GluN1 & 2 GluN2 (A–D) subunits

• Require glutamate (binds GluN2) & glycine (binds GluN1) for activation

• Channel permeable to Na⁺, Ca²⁺ & K⁺

• Blocked by Mg²⁺ at resting potential → needs depolarisation to unblock

• Involved in seizure initiation & spread

• Felbamate is an anti-epileptic drug that blocks NMDA receptors but has severe side effects

How do AMPA & NMDA receptors work together in excitatory responses?

• AMPA & NMDA receptors co-exist at most excitatory synapses

• Glutamate activates AMPA receptors first = small EPSP via Na⁺ influx

• This depolarisation removes Mg²⁺ block from NMDA channels

• NMDA receptors then activate = larger EPSP via Na⁺ & Ca²⁺ influx

What are the key features of kainate receptors?

• Limited brain distribution & less defined function

• Activated by glutamate; selectively by kainate

• Built from GluK1–3 (low glutamate affinity) & GluK4–5 subunits

• GluK1–3 + GluK5 form fully functional receptors

• Channel permeable to Na⁺, K⁺, & some to Ca²⁺

• Present pre- & postsynaptically

How do metabotropic glutamate receptors (mGluRs) work?

• Slow-acting, G-protein coupled receptors

• Glutamate binding = receptor conformational change

• Activates associated G-proteins (α, β, γ subunits)

• Subunits dissociate & bind intracellular targets

• Modulate ion channels & other effectors = slow ↑ in neuronal excitability

How does metabotropic glutamate receptor (mGlu1/mGlu5) signalling lead to a slow excitatory response?

• Glutamate binds to mGlu1 or mGlu5

• Activates G-proteins and dissociation of αq subunit

• αq activates phospholipase C to hydrolyse PIP2 into IP3 & DAG

• IP3 binds to receptors on ER = opens Ca2+ channels = ↑ cytosolic [Ca2+]

• DAG remains in membrane as a cofactor for PKC activation

• PKC & Ca2+ together = ↑ phosphorylation of targets = ↑ neuronal excitability

How does metabotropic glutamate receptor (mGlu2–8) signalling lead to a slow inhibitory response?

• Glutamate binds to mGlu2/3 or mGlu4/6/7/8

• Activates G-proteins and dissociation of αi subunit

• αi binds to adenylyl cyclase = ↓ cAMP production

• ↓ cAMP = inhibition of excitation

What are some other excitatory neurotransmitters & their receptors?

• Acetylcholine

  • Ionotropic nicotinic receptors = depolarisation

  • Metabotropic muscarinic receptors = inhibit voltage-gated K⁺ channels → depolarisation

• Serotonin

  • Ionotropic 5HT₃ receptors = depolarisation

• Dopamine & noradrenaline

  • Excitatory or inhibitory depending on signalling pathway & location

• Nitric oxide (NO)

  • Gas neurotransmitter = activates presynaptic cGMP signalling → excitatory effect

• Neuropeptides

  • Indirect excitatory or inhibitory effect depending on receptor & signalling pathway