Session 2 Flashcards
What are Glia?
Glia support, nourish and insulate neurones and remove ‘waste’ – around 10^12 glia compared to around 10^11 neurones in the CNS
Types of glial cells (neuroglia)
• Astrocytes (several different types) – most abundant type of glial cell – Supporters
• Oligodendrocytes – Insulators
• Microglia – immune response
Describe the role of astrocytes
- Structural support
- Help to provide nutrition for neurones – glucose-lactate shuttle
- Remove neurotransmitters (uptake) – control concentration of neurotransmitters (especially important for glutamate (toxic))
- Maintain ionic environment – K+ buffering
- Help to form blood brain barrier
How do astrocytes help provide energy for neurones?
- Neurones do not store or produce glycogen
- Astrocytes can store glycogen. This glycogen can be broken down into glucose to produce lactate. There is a transporter present in the cell membranes of the astrocyte and the neurone which can transport the lactate into the neurone which can then be converted into pyruvate which s used as a source of energy. This is importnat whne the neurones are very active as the astrocyte can supplement the neurone’s supply of glucose via this glucose lactate shuttle.
How do astrocytes help to remove neurotransmitters?
• Re-uptake – Astrocytes have transporters for transmitters such as glutamate so remove them from the synaptic cleft which helps to keep the extracellular concentration low. This is important so that the neurone can respond again to another incoming impulse but also becuase if glutmate builds up, it is toxic to neurones. This is called excitotoxixity - Too much excitment means that too much calcium enters into your post synaptic cells which can kill them.
slide 6
How do astrocytes help to buffer K+ in brain ECF?
During polarisation of the neurone sodium ions enter the neurone and then during repolarisation, poassium leaves the neurone. In areas where you have highly active neurones in a confined space, you can get a build of potassium in the ECF. When too high, it will cause the innappropriate depolarisation of neurones therefore potassium levels in the brain ECF need to be highly regulated. Astrocytes have a very negative resting membrane potentital (more negative than neurones) so you get inward movement of potassium ions into the astrocytes to help buffer ECF potassium concentration. This uptake occurs through potassium channels, sodium potassium ATPase and sodium potassium 2 chloride transporters. Astrocytes are coupled together to further potentiate their ability to buffer ECF potassium concentrations.
Role of oligodendrocytes?
- Responsible for myelinating axons in CNS
- Compare with PNS where Schwann cells are responsible for myelination
Schwann cells wrap around only one neurone whereas oligodendrocytes wrap around multiple.
What are microglia?
- Immunocompetent cells - like macrophages of the brain.
- Recognise foreign material - activated
- Phagocytosis to remove debris and foreign material
- Brain’s main defence system
Dendritic in it’s resting phase and then when activated dendrites thicken until it reaches its mature form where it can phagocytose the foreign material.
What is The Blood Brain Barrier?
- Limits diffusion of substances from the blood to the brain extracellular fluid
- Maintains the correct environment for neurones
- Brain capillaries have:
– tight junctions between endothelial cells prevents things like ions getting through.
– basement membrane surrounding capillary
– end feet of astrocyte processes which help form tight junctions. astrocytes have receptors and can respond to neurotransmitters.
What are the pathways across the blood brain barrier?
Lipid soluble molecules like oxygen and carbon dioxide can freely move through cell membranes so are not limited by the blood brain barrier.
In other capillaries where small molecules like ions and glucose can pass through the gaps between the endothelial cells, this doesn’t happen in capillaries in the brain due to tight junctions between endothelial cells prevtning them passing through. This means that substances need to be transported to the brain so their concentrations can be regulated.
• Substances such as glucose and amino acids and potassium are transported across the blod brain barrier via specific channels.
Why is the CNS described as Immune privileged (immune specialised)
- Does not undergo rapid rejection of allografts
- Rigid skull will not tolerate volume expansion – Too much inflammatory response would be harmful
- Microglia can also act as antigen presenting cells
- T-cells can enter the CNS
- CNS inhibits the initiation of the pro-inflammatory T-cell response
- Immune privilege is not immune isolation, rather specialisation
Describe the typical neuronal structure
Four main sections: • cell soma • dendrites • axon • terminals
Describe neurotransmitter release at the synapse
- Depolarisation in the terminal opens voltage-gated Ca2+ channels. Ca2+ ions enter the terminal
- Vesicles fusewith the membrane and release transmitter
- Neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane
Describe the postsynaptic response to neurotransmittter release
• The response depends on
– nature of transmitter
– nature of receptor:
- Ligand-gated ion channels
- G-protein-coupled receptors
How can we classify neurotransmitters in the CNS?
• Can be divided into three chemical classes:
AMINO ACIDS - glutamate, GABA, glycine
BIOGENIC AMINES - acetylcholine, noradrenalin dopamine, serotonin (5-HT), histamine,
PEPTIDES - dynorphin, enkephalins, substance P, somatostatin cholecystokinin neuropeptide Y
Summarise amino acid neurotransmitters
• excitatory amino acids:
– mainly glutamate - major neurotransmitter in the CNS
– major excitatory neurotransmitter
- over 70% of all CNS synapses are glutamatergic
- present throughout the CNS
• inhibitory amino acids:
– GABA
– Glycine
Describe the types of glutamate receptor and their role along with their synaptic plasticity and excitotoxicity
Two main types, Ionotropic and Metabotropic
Ionotropic have an integral ion channel associated with them. Their activation causes depolarisation due to inward movement of ions - results in increased excitability. Three types - AMPA receptors (Na+/K+ ion channel permeability), Kainate receptors (Na+/K+ ion channel permeability) and NMDA receptors (Na+/Ca2+ ion channel permeability). AMPA and NMDA receptors are mainly present at the synapses and are responsibe for the fast excitatory neurotransmitter responses.
Metabotropic receptors are G-protein coupled receptors, and theres roughly 7 types of metabotropic receptor. Linked to either changes in IP3 and calcium ion mobilisation or inhibition of adenylate cyclase and decreased cAMP levels. Main type to remember - mGluR1-7
Glutamate receptors, synaptic plasticity and excitotoxicity
• Glutamate receptors have an important role in learning and memory
– Activation of NMDA receptors (and mGluRs) can up-regulate AMPA receptors
– Strong, high frequency stimulation causes long term potentiation (LTP). Long term poteniation is a process where synapses are potentiated over a long term and thats what underlies learning and memory and how synapses are strengthened. Calcium levels dictate whether the synapse will be potentiated or depressed.
– Ca2+ entry through NMDA receptors important for induction of LTP
• Too much Ca2+ entry through NMDA receptors causes excitotoxicity
– Too much glutamate - excitotoxicity - e.g if a patient has a stroke then there will be an initial area where cells are deprived of oxygen causing them to die which will cause potassium levels to rise which causes depolarisation in surrounding neurones which causes the release of glutmate and so you get mor NMDA activation causing more calcium uptake causing further damage
Describe fast excitatory responses in neurones.
• Excitatory neurotransmitters cause depolarisation of the postsynaptic cell by acting on ligand-gated ion channels.
- excitatory postsynaptic potential (EPSP)
- depolarisation causes more action potentials
GABA and Glycine Receptors
- GABAA and glycine receptors have integral Cl- channels
- Opening the Cl- channel causes hyperpolarisation as chloride ions enter the cell which causes an Inhibitory post-synaptic potential (IPSP) which results in decreased action potential firing.
Note: There are also GABAB G-protein coupled receptors – these have a modulatory role
Which amino acid is in high concentration in the spinal cord and brainstem?
Glycine is present in high concentration in the spinal cord and brainstem
Patellar reflex - if you hit the pateller tendon with a hammer, youll get a knee jerk relfex. Contraction of the quadriceps and simulatneous relaxation of the hamstrings. Stretch in the quadriceps which activates some glutamatergic neurones which then transmit back to the spinal cord, release glutamate to activate the motor neurone which releases acetyl choline to cause contraction of the quadriceps. The glutamatergic afferent neurones also synapse with interneurones in the spinal cord. These interneurones are glycinergic neurones and they synapse on the motor neurones for the reciprocal group of muscles (hamstrings) and so they’re going to cause relaxation as glycine is an inhibitory neurotransmitter.
Inhibitory interneurones in the spinal cord release glycine
Cholinergic pathways in the CNS
- Neurones originate in basal forebrain and brainstem in Nucleus basalis which gives diffuse projections to many parts of cortex and hippocampus
- There are also local cholinergic interneurones • eg in corpus striatum
- These neurones are involved in arousal, learning & memory, motor control
- Degeneration of cholinergic neurones in the nucleus basalis is associated with Alzheimer’s disease
- Cholinesterase (breaks down acetyl choline) inhibitors are used to alleviate symptoms of Alzheimer’s disease
Dopaminergic pathways in the CNS
Explain how dopamine therapy can be used to treat Parkinson’s disease.
Levodopa given as treatment which is a precursor of dopamine. It can cross the blood brain barrier very easily. In both the periphery and brain there is an enzyme called aromatic amino acid decarboxylase. Howver you don’t want increased levels of dopamine in the periphery so carbidopa is given alongside levodopa which inhibits aromatic amino acid decarboxylase in the periphery as it can’t pass the blood brain barrier.
Noradrenaline and Noradrenergic pathways in the CNS
- Noradrenaline - transmitter at postganglionic – effector synapse in ANS
- Also acts as a neurotransmitter in the CNS
- Operates through G protein-coupled α- and β-adrenoceptors
- Receptors to noradrenaline in the brain are the same as in the periphery
Serotonergic pathways in the CNS
Serotonin / 5-Hydroxytryptamine
• Similar distribution to noradrenergic neurones - poject from Raphe nuclei.
FUNCTIONS :
- Sleep/wakefulness
- Mood
- SSRIs (serotonin selective reuptake inhibitors) treatment of depression and anxiety disorders
