S2) Cellular Physiology of the Brain

Question 1

The central nervous system is composed of a network of neurones with supporting glia.

Describe their respective roles

Answer 1

• Neurones sense changes and communicate with other neurones (approx. 10¹¹ neurones)
• Glia support, nourish and insulate neurones and remove ‘waste’ (approx. 10¹² glia)

Question 2

Identify and describe the three different types of glial cells

Answer 2

• Astrocytes – most abundant type of glial cell, supporters
• Oligodendrocytes – insulators
• Microglia – immune response

Question 3

Describe the five different roles of astrocytes

Answer 3

• Structural support
• Help with nutrition for neurones (glucose-lactate) shuttle
• Control [neurotransmitters] through uptake
• Maintain ionic environment (K⁺ buffering)
• Help form blood-brain barrier

Question 4

In four steps, explain how astrocytes help provide energy for neurones

Answer 4

⇒ Neurones do not store/produce glycogen

⇒ Astrocytes produce lactate which can be transferred to neurones

⇒ Supplements their supply of glucose

⇒ Glucose-lactate shuttle

Question 5

Explain how astrocytes help to remove neurotransmitters

Answer 5

• Astrocytes have transporters for transmitters such as glutamate
• This helps to keep the [extracellular] low in order to limit response and reduce toxicity

Question 6

Explain how astrocytes help to buffer K⁺ in brain ECF

Answer 6

• High levels of neuronal activity could lead to a rise in [K⁺] in brain ECF
• Astrocytes have a very negative RMP to facilitate the uptake of K⁺ to prevent over-excitation of neurones

Question 7

What do oligodendrocytes do?

Answer 7

Oligodendrocytes are responsible for myelinating axons in CNS

Question 8

Describe the structure and function of microglia cells

Answer 8

• Structure: immunocompetent cells
• Function: once activated, recognise foreign material and remove debris and foreign material by phagocytosis

Question 9

What is the purpose of the blood-brain barrier?

Answer 9

• Limits diffusion of substances from the blood to the brain extracellular fluid
• Maintains the correct environment for neurones

Question 10

Describe the features of capillaries in the blood brain barrier

Answer 10

• Tight junctions between endothelial cells
• Basement membrane surrounding capillary
• End feet of astrocyte processes

Question 11

Which substances can pass freely across the BBB?

Answer 11

Substances such as glucose, amino acids and potassium are transported across BBB

Question 12

Describe the typical neuronal structure

Answer 12

Four main sections:

• Cell soma
• Dendrites
• Axon
• Terminals

Question 13

In five steps, describe the processes occurring in neurotransmission across a synapse

Answer 13

⇒ Depolarisation in the terminal

⇒ Voltage-gated Ca²⁺ channels open

⇒ Ca²⁺ enter the terminal

⇒ Vesicles fuse and release transmitter

⇒ Neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane

Question 14

Which factors determine the postsynaptic response?

Answer 14

• Nature of transmitter
• Nature of receptor (KLING)

Question 15

Identify the three chemical classes of neurotransmitters and provide some examples for each

Answer 15

• Amino acids e.g. glutamate, GABA, glycine
• Biogenic amines e.g. acetylcholine, noradrenaline, dopamine, serotonin
• Peptides e.g. substance P, somatostatin, neuropeptide Y

Question 16

What are the two types of amino acid neurotransmitters?

Answer 16

• Excitatory amino acids – mainly glutamate (over 70% of all CNS synapses are glutamatergic)
• Inhibitory amino acids – GABA, Glycine

Question 17

Identify and describe the two types of glutamate receptors

Answer 17

• Ionotropic – ion channel is permeable to Na⁺ and K⁺, activation causes depolarisation e.g. AMPA & NMDA receptors
• Metabotropic – GPCR linked to changes in IP₃ and Ca²⁺ mobilisation / inhibition of AC and decreased cAMP levels

Question 18

Explain how the fast excitatory response occurs

Answer 18

• Excitatory neurotransmitters cause depolarisation of the postsynaptic cell by acting on ligand-gated ion channels (EPSP)
• Depolarisation causes more action potentials

Question 19

Glutamatergic synapses have both AMPA and NMDA receptors.

How do these receptors differ?

Answer 19

• AMPA receptors mediate the initial fast depolarisation
• NMDA receptors are permeable to Ca²⁺ and need glutamate binding and cell depolarisation to allow ion flow through the channel

Question 20

Explain how glutamate receptors have an important role in learning and memory

Answer 20

• Activation of NMDA receptors can up-regulate AMPA receptors
• Strong, high frequency stimulation causes long term potentiation (LTP)
• Ca²⁺ entry through NMDA receptors important for induction of LTP

Question 21

What happens when too much Ca²⁺ enters through NMDA receptors?

Answer 21

• Too much Ca²⁺ entry through NMDA receptors causes excitotoxicity
• Too much glutamate – excitotoxicity

Question 22

Where do the different inhibitory amino acid neurotransmitters act on the CNS?

Answer 22

• GABA is the main inhibitory transmitter in the brain
• Glycine acts as an inhibitory neurotransmitter mostly in the brainstem and spinal cord

Question 23

Explain the mechanism of action for GABA and Glycine

Answer 23

• GABA_A and glycine receptors have integral Cl^- channels
• Opening the Cl^- channel causes hyperpolarisation
• The inhibitory post-synaptic potential (IPSP) leads to decreased action potential firing

Question 24

What do barbiturates and benzodiazepines do?

Answer 24

• Barbiturates and benzodiazepines bind to GABA_A receptors
• Both enhance the response to GABA

Question 25

Describe the effects and use of barbiturates

Answer 25

- **Effects**: anxiolytic and sedative actions (risk of fatal overdose also dependence and tolerance) - **Use**: sometimes used as anti-epileptic drugs

Question 26

Describe the effects and use of benzodiazepines

Answer 26

- **Effects**: sedative and anxiolytic actions - **Use**: treats anxiety, insomnia and epilepsy

Question 27

Glycine is present in high concentration in the spinal cord and brainstem. Explain how it is released

Answer 27

**Inhibitory interneurones** in the spinal cord release glycine

Question 28

How do biogenic amines act?

Answer 28

Biogenic amines mostly act as **neuromodulators** and are confined to specific pathways

Question 29

ACh is also a central neurotransmitter. Explain how it acts in the CNS

Answer 29

- ACh acts at both **nicotinic** and **muscarinic receptors** in the brain - It is mainly **excitatory** and receptors are often present on **presynaptic terminals** to enhance the release of other transmitters

Question 30

Describe the course of cholinergic pathways in the CNS

Answer 30

- Neurones originate in **basal forebrain** and **brainstem** and give diffuse projections to **many parts of cortex** and **hippocampus** - There are also **local cholinergic interneurones** *e.g. in corpus striatum*

Question 31

What is the role of cholinergic pathways in the CNS?

Answer 31

**Cholinergic pathways** are involved in arousal, learning & memory, motor control

Question 32

Describe the relationship of cholinergic pathways in the CNS with Alzheimer's disease and the significance of this

Answer 32

- **Degeneration of cholinergic neurones** in the nucleus basalis is associated with Alzheimer’s disease - **Cholinesterase inhibitors** are used to alleviate symptoms of Alzheimer’s disease

Question 33

What is the role of dopaminergic pathways in the CNS?

Answer 33

Question 34

Identify two conditions associated with dopamine dysfunction

Answer 34

- Parkinson's disease - Schizophrenia

Question 35

Describe the cause and treatment of Parkinson's disease

Answer 35

- **Cause**: associated with loss of dopaminergic neurones – substantia nigra input to corpus striatum - **Treatment**: levodopa – converted to dopamine by DOPA decarboxylase (AADC)

Question 36

Describe the cause and treatment of schizophrenia

Answer 36

- **Cause**: may be due to release of too much dopamine - **Treatment**: antipsychotic drugs are antagonists at dopamine D₂ receptors

Question 37

Illustrate the use of dopamine therapy at the BBB in the treatment of Parkinson's disease

Answer 37

Question 38

Noradrenaline also acts as a neurotransmitter in the CNS. Explain how it acts in the CNS

Answer 38

- Operates through **G protein-coupled** α- and β-adrenoceptors - Receptors to NA in the brain are the same as in the periphery

Question 39

What is the role of noradrenergic pathways in the CNS?

Answer 39

Question 40

Describe the course and role of seratonergic pathways in the CNS

Answer 40

- **Course**: similar distribution to noradrenergic neurones - **Function**: sleep/wakefulness, mood

Question 41

Where is the majority of noradrenaline in the brain found?

Answer 41

Most NA in the brain comes from a group of neurones in the locus coeruleus

Question 42

Describe the relationship between noradrenaline and behavioural arousal

Answer 42

- **LC neurones** inactive during sleep - Activity increases during **behavioural arousal** - **Amphetamines** increases release of NA and dopamine → increase wakefulness - **Depression** may be associated with a deficiency of NA