Cellular Physiology of the brain Flashcards
What are the major cellular components of the nervous system?
- Neurones
- Glia
What are the major types of glia found in the CNS?
- Astrocytes (most abundant)
- Oligodendrocytes
- Microglia
What are the functions of astrocytes?
- Structural support
- Help to provide nutrition for neurones
- Remove neurotransmitters
- Maintain ionic environment
- Help to form blood brain barrier
- Can react to CNS trauma, helping to form scar tissue and to repair damage
- Take part in synaptic function
How do astrocytes help provide energy for neurones?
- Neurones do not store or produce glycogen
- Rely on glucose from blood
- When glucose delivery to neurone via blood is low, astrocytes can support neurones for a short while
- Via glucose-lactate shuttle
Outline how the glucose-lactate shuttle works
- Astrocytes produce lactate
- Lactate shuttled across to neurones via MCT1/MCT2 transporters
- Lactate is converted to pyruvate in neurones
- Pyruvate used to release ATP
How do astrocytes help to remove neurotransmitters?
- Have transporters for transmitters such as glutamate
- Astrocyte processes lie very close to synaptic terminals to keep glutamate concentrations low
- Keeps extracellular concentrations low
- Allows termination of synaptic response
- Cell doesn’t remain in permanently depolarised state
How do astrocytes help to buffer K+ in brain ECF?
- When neurones are very active they fire lots of APs
- K+ moves out into extracellular space
- If cells are very active [K+] can get very high
- Increased [K+] depolarises neurones and causes a positive feedback effect
- Results in lots of unwanted activity
- Astrocytes have a very negative cell membrane potential very close to K+ equilibrium potential
- Ion channels and transporters allow K+ to move into astrocytes e.g. Na+/K+ ATPase
- Astrocytes are coupled to one another and ions move between them
What is the function of oligodendrocytes?
- Responsible for myelinating axons in CNS
- Schwann cells are responsible for myelinating PNS
What is the function of microglia?
- Immunocompetent cells
- Have long dendrites
- When microglia recognise foreign material, they become activated
- Dendrites swell and cells become phagocytic
- Remove debris and foreign material
- Brain’s main defence system
- Can also act as antigen presenting cells
What forms the blood brain barrier?
- Endothelial cells of capillaries
What does the blood brain barrier do?
- Limits diffusion of substances from blood to brain extracellular fluid
- Maintains correct environment for neurones
Describe the structure of brain capillaries
- Tight junctions between endothelial cells - prevents molecules from freely diffusing across capillaries
- Basement membrane surrounding capillary
- End feet of astrocyte processes
What pathways exist across the blood brain barrier?
- H2O, CO2 and O2 can freely diffuse across the BBB
- Substances such as glucose, amino acids, potassium are transported across
Why do we need to control ion concentration across the blood brain barrier?
- Exercise can increase K+ levels in blood
- Don’t want K+ to cross BBB
- Otherwise it will cause unwanted neuronal activity
- Also need to limit amino acids from crossing BBB as these can act as neurotransmitters
Why is the CNS immune privileged?
- Rigid skull will not tolerate volume expansion
- Too much inflammatory response would be harmful
- Microglia can act as antigen presenting cells
- T cells can enter CNS
- CNS inhibits initiation of pro-inflammatory T cell response
- CNS is immune specialised, not isolated
What are the four main sections of a typical neurone?
- Cell soma
- Dendrites
- Axon
- Terminals
Outline what happens after neurotransmitter is released
- Depolarisation in terminal
- Voltage-gated Ca2+ channels open
- Ca2+ enter terminal
- Vesicles fuse and release transmitter
- Neurotransmitter diffuses across synaptic cleft
- Binds to receptors on post-synaptic membrane
Outline the post-synaptic response
- Depends on nature of transmitter and nature of receptor (ligand-gated or GPCR)
What are the three classes of neurotransmitters?
- Amino acids
- Biogenic amines
- Peptides
What are some examples of amino acid neurotransmitters?
- Glutamate - excitatory
- GABA - inhibitory
- Glycine - inhibitory
What are the two basic classes of glutamate receptors?
- Ionotropic
- Metaboptropic
What are the different types of ionotropic receptors?
- AMPA receptors (Na+/K+)
- Kainate receptors (Na+/K+)
- NMDA receptors (Na+/K+ and Ca2+)
- Ion channel permeable to Na+ and K+ (and in some cases Ca2+ ions)
- Activation causes depolarisation - increased excitability
What is the metabotropic receptor for glutamate like?
- G protein coupled receptor
- Linked to either: changes in IP3 and Ca2+ mobilisation
- Or inhibition of adenylate cyclase and decreased cAMP levels
Outline fast excitatory responses
- Excitatory neurotransmitters
- Allows cations to influx into cells
- Causes depolarisation in postsynaptic terminal
- This is an excitatory postsynaptic potential (EPSP)
- Depolarisation causes more action potentials
What happens if an EPSP exceeds the threshold potential?
- Action potentials are triggered
- Large amounts of transmitter in synapse cause increased magnitude of of EPSP and increased frequency of APs
What are glutamatergic synapses like?
- Very important, particularly in learning and memory
- AMPA and NMDA receptors work together
How do glutamatergic synapses work?
- Glutamatergic synapses have both AMPA and NMDA receptors
- AMPA receptors mediate initial fast depolarisation
- Glutamate activates these receptors
- This allows removal of Mg2+ ion from pore of NMDA receptor
- Makes them permeable to Ca2+
- Glycine acts as a co-agonist
What is long term potentiation?
- If synapse is strongly activated, lots of glutamate is released and additional AMPA receptors are inserted into postsynaptic membrane
- Ca2+ entry through NMDA receptors important for induction of LTP
- Extra AMPA means that synapse will transmit more readily
- Molecular basis for learning and memory
What happens if too much Ca2+ enters through NMDA receptors?
- Causes excitotoxicity
- Also, if all synapses were to strengthen, they would rapidly reach saturation and information could not be stored
How do we prevent too much Ca2+ enters through NMDA receptors?
- Long-term depression
- Actively downregulates strength of glutamatergic synapses
- May contribute to forgetting
What are the inhibitory amino acid neurotransmitters?
- GABA is main inhibitory transmitter in brain
- Glycine acts mostly in brainstem and spinal cord
What are the GABA receptors?
- Ionotropic - GABAA
- Metabotropic - GABAB (GPCR with modulatory roles)
How do the GABAA receptors work?
- Permeable to Cl- (have integral Cl- channels)
- Opening Cl- channels leads to influx into cell
- Hyperpolarisation
- Causes inhibitory postsynaptic potential
- Leads to decreased action potential firing
Which drugs bind to GABAA receptors?
- Barbiturates
- Benzodiazepines
- Enhance response to GABA
What are the uses of barbiturates?
- Rarely used nowadays
- Risk of fatal overdose, dependence and tolerance
- Sometimes used as anti-epileptic drugs
What are the uses of benzodiazepines?
- Used as sedatives and anxiolytics
- Addictive
- Treat anxiety, insomnia, epilepsy
Outline what glycine is like as a neurotransmitter
- Inhibitory
- Less widespread than GABA
- Released in spinal cord during REM sleep, causing paralysis
- Receptors are same as GABA receptors
What is the role of other neurotransmitters in the CNS?
- Have a more modulatory role
- Involved in discrete pathways
Give examples of biogenic amines and acetylcholine
- Acetylcholine
- Dopamine
- Noradrenaline
- Serotonin
- Mostly act as neuromodulators
- Confined to specific pathways
Where is ACh found in the CNS?
- Neuromuscular junction
- Ganglion synapse in ANS
- Postganglionic parasympathetic
- Also a central neurotransmitter
What is the role of ACh in the CNS?
- Central neurotransmitter
- Acts at both nicotinic and muscarinic receptors in brain
- Mainly excitatory
- Receptors often present on presynaptic terminals to enhance release of other transmitters
Outline the key pathways involving ACh in the CNS
- Arousal - anticholinergic drugs may cause drowsiness
- Learning and memory - cholinesterase inhibitors treat Alzheimer’s
- Motor control - cholinergic drugs treat Parkinson’s
Outline the cholinergic pathways in the CNS
- Discrete groups of neurones originate in basal forebrain and brainstem (nucleus basalis)
- Give diffuse projections to many parts of cortex and hippocampus
- Also local cholinergic interneurons e.g. in corpus striatum, thalamus, substantia nigra
What is associated with Alzheimer’s disease?
- Degeneration of cholinergic neurones in nucleus basalis
- Cholinesterase inhibitors are used to alleviate symptoms of Alzheimer’s
Which key pathways involve dopamine (DA)?
- Nigrostriatal
- Neocortical
- Mesolimbic
Outline the nigrostriatal pathway
- DA
- From substantia nigra to striatum
- Important for motor control
- Degeneration of this pathway causes Parkinson’s
Outline the neocortical pathway
- DA
- From midbrain to cerebral cortex
- Mood, arousal and reward
Outline the mesolimbic pathway
- DA
- From midbrain to limbic system
- Mood, arousal and reward
- Overactivity in this pathway may contribute to schizophrenia
- Amphetamines release dopamine and noradrenaline - produce schizophrenic like behaviour
How can Parkinson’s disease be treated?
- Levodopa - converted to dopamine by aromatic amino acid decarboxylase (AADC)
How do antipsychotic drugs work on?
- As antagonists at dopamine D2 receptors
How does levodopa interact with the BBB?
- L-DOPA is converted to dopamine by AADC in brain
- L-DOPA crosses BBB readily via Large Neutral Amino Acid transporter (LNAA)
- L-DOPA can also be converted in periphery by AADC
- High levels of dopamine cause side effects affecting heart, GI tract and urinary system
- Carbidopa is co-administered
- Inhibits peripheral AADC
- Does not cross BBB so production of dopamine from L-DOPA is not affected
How does noradrenaline (NA) operate?
- Released by sympathetic postganglionic terminals
- Operates through GPCRs (adrenoceptors) - similar both in brain and periphery
Which key pathways involve noradrenaline?
- Cell bodies are found in brainstem
- Project to widespread areas including cortex, limbic system and cerebellum
- Involved in behavioural arousal
Where does most NA in the brain come from?
- Locus coeruleus
- Locus coeruleus neurones inactive during sleep
- Activity increases during behavioural arousal
- Amphetamines increase release of NA and increase wakefulness
- Low levels of NA are associated with depression
Outline the serotonergic pathways in the CNS
- Serotonin, 5-HT
- Similar distribution to NA neurones - originates from raphe nuclei of brainstem
- Involved in sleep and wakefulness and regulation of mood
- Low levels of serotonin cause depression
What do SSRIs do?
- Selective serotonin reuptake inhibitors increase levels of serotonin in brain
- Can help with depression and anxiety disorders
What is the role of histamine in the CNS?
- Has a role in sleep and wakefulness
- Stimulates cortex, maintains wakefulness
- Some antihistamines can cause drowsiness by antagonising this action
Outline the role of peptides in the CNS
- Diffuse slowly
- Sometimes widespread
- Often alongside other transmitters, modulatory action
- Dynorphin and encephalins involved in pain transmission
