3. Cellular physiology of the brain Flashcards
What are the Components of the central nervous system?
Network of neurones with supporting glia
function of neurones
• Neurones sense changes and communicate with other neurones
function of glial cells
Glia support, nourish and insulate neurones and remove ‘waste’
What are the different types of glial cells?
Astrocytes, microglia, oligodendrocytes
What are the functions of astrocytes? (5)
- structural support
- provide nutrition for neurones
- remove neurotransmitters (uptake)
- maintain ionic environment (K+ buffering)
- help to form blood brain barrier
Do neurones have stores of glycogen?
No, do not store or produce glycogen
How do astrocytes provide energy for neurones?
- have glycogen store which is converted to pyruvate and then lactate
- produce lactate which can be transferred to neurones
- produce lactate which can be transferred to neurones
- supplements their supply of glucose
- lactate can be converted to pyruvate in neurone to produce ATP
- used when glucose supply reduced
What is the mechanism by which astrocytes provide lactate to neruones?
Glucose lactate shuttle
- Monocarboxylate transporters used (MCT1 and MCT2)
Why is uptake of neurotransmitter important by astrocytes, uptake of which one is particularly important?
- toxic to neurones (excito-toxicity)
- allow response to occur again
Glutamate important - main excitatory neurotransmitter in the brain
how do Astrocytes help to remove neurotransmitters?
Re-uptake
– Astrocytes have transporters for transmitters such as glutamate
– Helps to keep the extracellular concentration low
Why is potassium buffering important?
- High levels of neuronal activity could lead to a rise in [K+] in brain ECF
- Raised [K+] in the ECF causes depolarisation of neurones and therefore inapproapriate activation of the neurones?
How do astrocytes help buffer K+?
- astrocytes have a relatively more negative resting membrane potential
- so have the ability to buffer excess potassium
- Na+/K+ ATPase, NKCC2, Potassium channels
(astrocytes are also coupled to each other, effectively buffer K+)
What is the functions of oligodendrocytes?
Myelinating axons in CNS
- one can myelinate several axons
What is the functions of microglia?
- immunocompetent cells
- recognise foreign material - activated
- phagocytosis to remove debris and foreign material
- brain’s main defence system
How does the appearance of microglia change?
- look like a star (thin projections from body)
- projections become thicker when they become activated
- look like a blob when phagocytic
What is the functions of the blood brain barrier?
- Limits diffusion of substances from the blood to the brain extracellular fluid
- Maintains the correct environment for neurones
What makes up the blood brain barrier?
- tight junctions between endothelial cells
- basement membrane surrounding capillary
- end feet of astrocyte processes
What is immune privilege?
Certain sites of the human body have immune privilege, meaning they are able to tolerate the introduction of antigens without eliciting an inflammatory immune response
Why is the CNS immune privileged?
Rigid skull will not tolerate volume expansion
- Too much inflammatory response would be harmful
(specialisation not immune isolation)
Can T cells enter the CNS?
Yes - antigen presenting cells present
- CNS inhibts the initiation of the pro-inflammatory T cell response
What are the different types of synapses in the CNS?
- fast excitatory neurotransmission
- fast inhibitory neurotransmission
- modulatory responses
What are the 4 main structures of neurones?
- cell soma
- dendrites
- axon
- terminals
what is transported across blood brain barrier?
- Substances such as glucose and amino acids and potassium are transported across BBB.
- This allows the concentration to be controlled
How is neurotransmitter released from the presynaptic terminal?
- Depolarisation in the terminal opens voltage-gated Ca2+ channels. Ca2+ ions enter the terminal
- Vesicles fuse and release transmitter
- Neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane
What does the response to release of neurotransmitter depend on?
- nature of transmitter
- nature of receptor
• Ligand-gated ion channels
• G-protein-coupled receptors
What are the 3 chemical classes of neurotransmitters? give examples
- Amino acids: glutamate, glycine and GABA
- Biogenic amines: acetylcholine, noradrenlaine, dopamine, serotonin, histamine
- Peptides: enkephalins, substance P, somatostain, CCK, Neuropeptide Y
What are the main excitatory and inhibitory neurotransmitters in the CNS?
Excitatory: glutamate
Inhibitory: GABA, glycine
WHat percent of CNS synpases are glutamatergic?
70%
What are the ionotropic receptors of glutamate and what are they permeable to?
- AMPA: Na+ and K+
- Kainate: Na+ and K+
- NMDA: Na+, K+ and Ca+
(influx of Na+ into postsynaptic cell)
What are the metabotropic receptors of glutamate and what are they linked to?
mGluR1 - mGluR7
Linked to either:
• changes in IP3 and Ca2+ mobilisation
• or inhibition of adenylate cyclase and decreased cAMP levels
What are fast excitatory responses?
Excitatory neurotransmitters cause depolarisation of the postsynaptic cell by acting on ligand-gated ion channels
- excitatory postsynaptic potential (EPSP)
depolarisation causes more action potentials
Which receptors mediate the initial fast depolarisation?
AMPAreceptors
What is different about the NMDA compared to AMPA receptors?
- permeable to calcium
- have magnesium ions blocking the pore preventing flow of ions
How is flow of ions through the NDMA receptors achieved?
Depolarisation of the post synaptic cell by AMPA receptors causes magnesium to be released from the pore of the NMDA receptors allow ions through.
which receptors are present on Glutamatergic synapses
• Glutamatergic synapses have both AMPA and NMDA receptors
what does NDMA receptors need?
NMDA receptors need glutamate to bind and the cell to be depolarised
to allow ion flow through the channel
WHat is the effect of glycine on NMDA receptors?
Acts as a co-agonist
What important role do NMDA receptors have?
Important role in learning and memory
How are NDMA receptors involved in learning and memory?
- Activation of NMDA receptors (and mGluRs) can up-regulate AMPA receptors
- Strong, high frequency stimulation causes long term potentiation (LTP)
- Ca2+ entry through NMDA receptors important for induction of LTP
what happens if Too much Ca2+ enter through NMDA receptors?
– Too much glutamate - excitotoxicity
What are the main inhibitory neutransmitters in the brain and spinal cord?
Brian: GABA, Spinal cord and brainstem: glycine
What type of receptors do GABA and glycine have?
Ionotropic, integral chloride ion channels
- inhibitory post synaptic potential
what effect does GABA and glycine have on receptors?
• Opening the Cl- channel causes hyperpolarisation
– Inhibitory post-synaptic potential (IPSP)
• Decreased action potential firing
What are 2 classes of drugs that enhance the response to GABA and what are they used to treat?
Barbiturates - anxiolytic and sedative actions, but not used for this now
• risk of fatal overdose also dependence and tolerance
• sometimes used as anti-epileptic drugs
Benzodiazepines
- have sedative and anxiolytic effects
- used to treat anxiety, insomnia and epilepsy
Give an example of glycine in the spinal cord?
Inhibitory interneurones in the spinal cord release glycine (deep tendon reflexes: inhibition of the antagonistic muscles)
describe the deep tendon reflex
- stretch receptors in muscle spindle of quadriceps detect stretch caused by hitting knee.
- an impulse sent along sensory afferent to dorsal root of spinal cord and into grey matter
- sensory afferent synapses and releases glutamate with motor efferents which cause quadriceps to contract
- sensory afferents also synapse with interneuron by releasing glutamate
- the interneuron releases glycine and synapses with another motor efferent to hamstrings which is inhibitory and causes hamstring relaxation
Where are acetylcholine often present in the brain and what do they do?
– neuromuscular junction
– ganglion synapse in ANS
– postganglionic parasympathetic
• ACh is also a central neurotransmitter
– acts at both nicotinic and muscarinic receptors in the brain
– mainly excitatory
– receptors often present on presynaptic terminals to enhance the release of other transmitters
What are the different cholinergic pathways in the brain?
- Nucleus basalis (basal forebrain): projects throughout the cortex
- substantia nigra to the thalamus
- corpus striatum (striatal interneurones)
- Septohippocampal nucleus to hippocampus
What are cholinergic pathways in the brain associated with?
Arousal, learning & memory, motor control
How is acetylcholine associated with alzeheimer’s disease and what can therefore be used to alleviate symptoms?
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
What are the 4 major dopamine pathways in the brain?
- Mesocortical pathway (ventral tegmental area in midbrain to prefrontal cortex)
- mesolimbic pathway (VTA to hippocampus, amygdala, nucleus accumbens)
- Nigrostriatal pathway (substantia nigrae to striatum)
- tubero-hypophyseal pathway
What are the general functions of the mesocortical and mesolimbic pathway? (3)
involved in mood, arousal and reward
What are the general function of the nigrostriatal pathway?
Motor control
What conditions are associated with dopamine dysfunction?
Parkinson’s disease
Schizophrenia
What is the relationship between dopamine and Schizophrenia and what is used to treat it?
• May be due to release of too much dopamine
- amphetamine releases dopamine & noradrenaline (schizophrenic behaviour)
- produces schizophrenic like behaviour
- antipsychotic drugs are antagonists at dopamine D2 receptors
What is the relationship between dopamine and parkinson’s disease?
- associated with loss of dopaminergic neurones
- substantia nigra input to corpus striatum
How can parkinson’s associated with dopamine dysfunction be treated?
Can be treated with levodopa, crosses the blood brain barrier through LNAA - converted to dopamine by DOPA aromatic amino acid decarboxylase (AADC)
What must be given with levodopa in dopamine therapy for parkinsons disease?
Carbidopa inhibits AADC in the periphery, preventing rise in dopamine there, but cannot cross the blood brain barrier so cannot inhibit AADC in the brain
What are the main noradrenergic pathways in the CNS?
From locus ceruleus (from the pons) to cortex, hypothalamus, amygdala, cerebellum
When is activity of neurones of the locus ceruleus low/high?
- low activity during sleep
- high activity during behavioural arousal
- amphetamines increases release of noradrenaline and dopamine and increase wakefulness
what is the action of noradrenalin and where does it act?
- 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
what is the association between noradrenaline and depression?
Relationship between mood and state of
arousal
– depression may be associated with a
deficiency of NA
What is the major serotonergic pathway in the CNS?
Raphe nuclei in the brainstem - wide distribution in the cortex, corpus striatum, thalamus, hypothalamuc, hipoocampus, amygdala, cerebellum
What are the functions of serotonin pathways in the CNS?
- Sleep/wakefulness
* Mood
What are SSRIs used for?
SSRIs (serotonin selective reuptake inhibitors) treatment of depression and anxiety disorders
