S2) Cellular Physiology of the Brain Flashcards
The central nervous system is composed of a network of neurones with supporting glia.
Describe their respective roles
- Neurones sense changes and communicate with other neurones (approx. 1011 neurones)
- Glia support, nourish and insulate neurones and remove ‘waste’ (approx. 1012 glia .: 10 x more)
Identify and describe the three different types of glial cells
- Astrocytes – most abundant type of glial cell, supporters
- Oligodendrocytes – insulators (insulate axons)
- Microglia – responsible for immune response in brain
Describe the five different roles of astrocytes
- Structural support
- Help with nutrition for neurones via the glucose-lactate shuttle (convert glucose to lactate which they transfer to neurones)
- Control [neurotransmitters] through uptake (help with its removal as if this was not taken up - it could lead to excessive activation of receptors e.g. high levels of glutamate conc is toxic)
- Maintain ionic environment (K+ buffering - esp in brain as large quantities of K+ is released in highly active brain )
- Help form blood-brain barrier (induce expression of tight junction between brain and endothelial cells)
What are some other functions of Astrocytes?
- Can react to CNS trauma, helping to form scar tissue and to repair damage
- Connected to each other via gap junctions which is thought to form a syncytium (calcium waves can propagate through this, which might contribute to cognitive function)
- It is also known that astrocytes take part in synaptic function (the so called tripartite synapse)
In four steps, explain how astrocytes help provide energy for neurones
⇒ Neurones do not store/produce glycogen (lack enzymes to produce glycogen .: rely on glucose only)
⇒ Astrocytes produce lactate which can be transferred to neurones via breakdown of glycogen. (Glycogen → Pyruvate → Lactate)
⇒ Supplements their supply of glucose
⇒ Glucose-lactate shuttle (if glucose levels are low, for short time → astrocytes can provide energy + support neurone via this shuttle mechanism)
Explain how astrocytes help to remove neurotransmitters
- Astrocytes have transporters for transmitters such as glutamate
- This helps to keep the [extracellular] low in order to limit response and reduce toxicity (high levels of glutamate is toxic)
Ensures synaptic response is ended so that cell can be ready to receive another synaptic neurone (doesn’t stay permanently depolarised)
Explain how astrocytes help to buffer K+ in brain ECF
- 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 .: Astrocytes take up K+ ions to prevent rise of [K+] in brain ECF as high [K+] in brain ECF can result in unwanted depolarisation of neurones (more active, more they depolarise) .: dangerous for the brain!!!
What do oligodendrocytes do?
Oligodendrocytes are responsible for myelinating many axons in CNS .: helps with the quicker conduction of action potentials.
Schwann cells for PNS
Relatively small cells with many processes.
Damaged in multiple sclerosis
Describe the structure and function of microglia cells
- Structure: immunocompetent cells (major immune cell in the CNS)
- Function: once activated, recognise foreign material and remove debris and foreign material by phagocytosis
They are the brain’s main defence system
They will adapt their shape from dendritic to swelling up to becoming a phagocytic shape. (change their morphology)
- Remove debris and help clean up sites of damage
- On the flip side they may cause collateral damage, injuring cells that were not involved in the initial pathology
What is the purpose of the blood-brain barrier?
– It is critically important that homeostasis is tightly regulated in the brain
▪ Impaired homeostasis leads to disordered brain function (e.g. seizures
caused by electrolyte disturbances)
- Limits diffusion of substances from the blood to the brain extracellular fluid
- Maintains the correct environment for neurones
Describe the features of capillaries in the blood brain barrier
- Tight junctions between endothelial cells
- Basement membrane surrounding capillary
- End feet of astrocyte processes
Which substances can pass freely across the BBB?
It is a selectively permeable membrane, not an absolute barrier!
Lipophilic gases, CO2, O2, H20 can freely diffuse through lipid bilayer.
Substances such as glucose, amino acids and potassium are transported across BBB
Fat soluble molecules cross relatively easily
• Think about the general anaesthetic propofol – that white stuff that is given to send you to sleep. It is white because it is a lipid emulsion (like mayonnaise)
This allows the concentration to be controlled.
Describe how CNS has immune privileges.
- Does not undergo rapid rejection of allografts (The transplant of an organ, tissue, or cells from one individual to another individual of the same species who is not an identical twin)
- Rigid skull will not tolerate volume expansion
– Too much inflammatory response would be harmful (increased ICP .: cell death in brain if reduced perfusion) - Microglia can act as antigen presenting cells
- T-cells can enter the CNS
- CNS inhibits the initiation of the pro-inflammatory T-cell response (limit amount of inflammation)
- Immune privilege is not immune isolation, rather specialisation
Describe the typical neuronal structure
Four main sections:
- Cell soma (cell body)
- Dendrites
- Axon
- Terminals
(+ Synapses)
In five steps, describe the processes occurring in neurotransmission across a synapse
⇒ AP will travel down axon to pre-synaptic terminal and cause depolarisation in the terminal
⇒ Voltage-gated Ca2+ channels open
⇒ Ca2+ enter the terminal
⇒ causes Vesicles to fuse with pre-synaptic membrane and release transmitter
⇒ Neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane
⇒ Post-synaptic response
Which factors determine the postsynaptic response?
- Nature of transmitter - Excitatory (e.g. glutamate) vs Inhibitory (e.g. GABA)
- Nature of receptor (KLING) – Ligand gated ion channels (Receptors which contain ion channel) GPCRs (linked to intracellular signalling mechanism)
Many neurotransmitters have been identified in the CNS
They can be divided into 2 chemical classes.
Identify the three chemical classes of neurotransmitters and provide some examples for each
- Amino acids e.g. glutamate, GABA, glycine
- Biogenic amines e.g. acetylcholine, noradrenaline, dopamine, serotonin (5-HT)
- Peptides e.g. substance P, somatostatin, neuropeptide Y , cholecystokinin, dynorphin
What are the two types of amino acid neurotransmitters?
- Excitatory amino acids – mainly glutamate (over 70% of all CNS synapses are glutamatergic + present throughout the CNS)
- Inhibitory amino acids – GABA, Glycine (simplest amino acid)
Identify and describe the two types of glutamate receptors
- Ionotropic – ion channel is permeable to Na+ and K+ + in some cases Ca2+ ions, activation causes depolarisation .: increased excitability e.g. AMPA & NMDA receptors & Kainate receptors
- Metabotropic – GPCR linked to changes in IP3 and Ca2+ mobilisation / inhibition of Adenylate cyclase and decreased cAMP levels
Explain how the fast excitatory response occurs
- Excitatory neurotransmitters cause depolarisation of the postsynaptic cell by acting on ligand-gated ion channels (EPSP) – excitatory post synaptic potential (causes depolarisation in post-synaptic cell .: if depolarisation reaches threshold → get an increase in APs)
- Depolarisation causes more action potentials
Glutamatergic synapses have both AMPA and NMDA receptors.
How do these receptors differ?
- AMPA and NMDA receptors work together
- Initially, release of glutamate activates AMPA receptors which 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 - because the ion channel is normally blocked by Magnesium ions .: if you have lots of activation via AMPA receptor, this causes cell depolarisation .: depolarisation leads to removal of Mg ion in the pore of the NMDA receptor .: NMDA receptors can open + allow Ca2+ ions to flow into the postsynaptic terminal.
note: NMDA receptors - also glycine acts as a co-agonist (background levels of glycine facilitate this process, although best just to focus on glycine in its inhibitory role)
Explain how glutamate receptors have an important role in learning and memory
- AMPA and NMDA receptors work together
- 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 - long term potentiation .: strengthens the synapse - makes it last longer! - .: we get long term memory
- WORKBOOK NOTES BELOW
• If the synapse is activated strongly, and a lot of glutamate is released then additional AMPA receptors are inserted into the postsynaptic membrane
• This is mediated by the entry of Ca through NMDA receptors • Extra AMPA receptors means that the synapse will transmit more readily (i.e. it ‘stronger’
• This is the process of long term potentiation (LTP) which is the molecular basis for learning and memory
• However, if all synapses were to only strengthen they would rapidly reach ‘saturation’ and information could not be stored • Hence, the process of long term depression is in place which
actively downregulates the strength of glutamatergic synapses
• LTD may contribute to forgetting, but there are many mechanisms at play here
What happens when too much Ca2+ enters through NMDA receptors?
- Too much Ca2+ entry through NMDA receptors causes excitotoxicity
- Too much glutamate – excitotoxicity (can kill neurones .: vital to regular NMDA activity)
Where do the different inhibitory amino acid neurotransmitters act on the CNS?
- GABA is the main inhibitory transmitter in the brain
- Glycine acts as an inhibitory neurotransmitter mostly in the brainstem and spinal cord
How is glycine used as amino acid?
- Inhibitory
- Less widespread than GABA
- Released in the spinal cord during REM sleep to inhibit LMNs, causing paralysis
- Receptors
▪ Follow same principles as GABA receptors
▪ You don’t need to know much about these
Explain the mechanism of action for GABA and Glycine
- GABAA and glycine receptors have integral Cl- channels
- Opening the Cl- channel causes hyperpolarisation (inside of cell more neg .: bringing membrane potential further away from threshold of firing APs .: decreasing AP) - because as [Cl] inside the cell is lower than [Cl] outside, opening of GABAA receptors leads to Cl influx which hyperpolarises the cell causing an inhibitory postsynaptic potential (IPSP)
- The inhibitory post-synaptic potential (IPSP) leads to decreased action potential firing
What do barbiturates and benzodiazepines do?
- Barbiturates and benzodiazepines bind to GABAA receptors
- Both enhance the response to GABA (even alcohol increases the activity)
Describe the effects and use of barbiturates
- Effects: anxiolytic and sedative actions (rarely used now due to risk of fatal overdose also dependence and tolerance)
- Use: sometimes used as anti-epileptic drugs (reduces electrical activity of neurones in the brain)
Describe the effects and use of benzodiazepines
- Effects: sedative and anxiolytic (anti-anxiety) actions – be careful when prescribing these as they are addictive.
- Use: treats anxiety, insomnia and epilepsy
Glycine is present in high concentration in the spinal cord and brainstem.
Explain how it is released
Inhibitory interneurones in the spinal cord release glycine
Summary:
- Glutamate is the major excitatory transmitter
- GABA and Glycine are the main inhibitory neurotransmitters
- Other transmitters have more of a modulatory role in the CNS or are involved in discreet pathways
How do biogenic amines act?
Biogenic amines mostly act as neuromodulators and are confined to specific pathways
Identify examples of biogenic amines and Ach
- acetylcholine
- dopamine
- noradrenaline
- serotonin (5-HT)
Identify the general role of AcH
- neuromuscular junction (acts on nAcHr)
- ganglion synapse in ANS (between pre-ganglionic and post-ganglionic where it acts on nAchR)
- postganglionic parasympathetic (acts on mAchR)
- sympathethic cholinergic fibres (innervate sweat glands)
ACh is also a central neurotransmitter.
Explain how it acts in the CNS
- ACh acts at both nicotinic (ion channel) and muscarinic receptors (metabotropic) in the brain
- It is mainly excitatory and receptors are often present on presynaptic terminals to enhance the release of other transmitters e.g Ach facilitates the release of dopamine in the brain.
Describe the course of cholinergic pathways in the CNS
- 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, substantia niagra, thalamus
- (Produced by basal forebrain nuclei that project to widespread cortical areas and also present in interneurones in the basal ganglia)*
What is the role of cholinergic pathways in the CNS?
Cholinergic pathways are involved in arousal, learning & memory, motor control
Describe the relationship of cholinergic pathways in the CNS with Alzheimer’s disease and the significance of this
- Degeneration of cholinergic neurones in the nucleus basalis is associated with Alzheimer’s disease
- Cholinesterase inhibitors by enhancing amount of Ach available - are used to alleviate symptoms of Alzheimer’s disease
What is the role of dopaminergic pathways in the CNS?
-
Nigrostriatal (from substantia nigra to the striatum)
• Motor control • Degeneration of this pathway (i.e. loss of dopaminergic neurones) causes Parkinson’s disease - Neocortical (from the midbrain to the cerebral cortex) • Mood, arousal and reward
-
Mesolimbic (from the midbrain to the limbic system (i.e. hippocampus, amygdala etc)
• Mood, arousal and reward • Overactivity in this pathway may contribute to schizophrenia
o Amphetamine, which causes release of dopamine, can cause symptoms similar to schizophrenia
o Antipsychotic drugs antagonise dopamine receptors
Identify two conditions associated with dopamine dysfunction
- Parkinson’s disease
- Schizophrenia
Describe the cause and treatment of Parkinson’s disease
- Cause: associated with loss of dopaminergic neurones – from substantia nigra input to corpus striatum .: impact on motor control
- Treatment: levodopa/L-DOPA (pre-cursor of DOPA) – converted to dopamine by DOPA decarboxylase (AADC) (cholinergic drugs are sometimes used in the treatment of Parkinson’s disease)
Illustrate the use of dopamine therapy at the BBB in the treatment of Parkinson’s disease
Learn the table.
- L-DOPA crosses the BBB readily via the large neutral amino acid transporter (LNAA)
- The problem is that L-DOPA can also be converted to dopamine in the periphery by AADC
- High levels of dopamine in the periphery can cause side effects affecting the heart, GI tract and urinary system
- Hence, the peripheral conversion of L-DOPA to dopamine is inhibited by the co-administration of carbidopa, which is a peripheral AADC inhibitor
- Carbidopa does not cross the BBB, hence brain production of dopamine from L-DOPA is not affected
Describe the cause and treatment of schizophrenia
- Cause: may be due to release of too much dopamine → produces schizophrenic like behaviour
- Treatment: antipsychotic drugs are antagonists at dopamine D2 receptors
Noradrenaline - transmitter at postganglionic – effector synapse in ANS
Noradrenaline also acts as a neurotransmitter in the CNS.
Explain how it acts in the CNS
- Operates through G protein-coupled α- and β-adrenoceptors
- Receptors to NA in the brain are the same as in the periphery
What is the role of noradrenergic pathways in the CNS?
– project to widespread areas including cortex, limbic system and cerebellum
Where is the majority of noradrenaline in the brain found?
Most NA in the brain comes from a group of neurones in the locus coeruleus i.e cell bodies are found in the brainstem
Describe the relationship between noradrenaline and behavioural arousal
- 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 (drugs that increase NA in the brain - used to treat depression)
Describe the course and role of seratonergic, 5-HT pathways in the CNS
- Course: similar distribution to noradrenergic neurones (originates from the raphe nuclei of the brainstem)
- Function: involved in: sleep/wakefulness and regulation of mood
When can SSRIs (serotonin selective re-uptake inhibitors) be used?
It is though that low levels of serotonin causes depression .: can be used in
Treatment of depression and anxiety disorders
(inhibits re-uptake of serotonin .: more serotonin available in the brain)
What is histamine’s role?
- Role in sleep and wakefulness
- Histamine stimulates the cortex, maintains wakefullness
- Some antihistamines cause drowsiness by antagonising the action
How do peptides such as dynorphin, encephalins, orexin/ hypocretin work?
Peptides (diffuse slowly and sometimes widespread, often alongside other transmitters, modulatory action)
Dynorphin → Involved in pain transmission
Encephalins → involved in pain transmission
Orexin/ hypocretin → Interesting, given its role in narcolepsy
Summary:
