Neurones & glia Flashcards
Describe the ole of neurones and supporting glia which make up the CNS?
Neurones sense changes and communicate with each other
More glia which support, nourish and insulate neurones and remove waste
What are the three types of glial cells (neuroglia) and what are their general functions?
- astrocytes
Most abundant, supporters - oligodendrocytes
Insulators (produce myelin sheath, wrap around multiple axons whereas PNS Schwann cells responsible) - microglia
Brain immune response
In depth role of astrocytes
Structural support
- Provide nutrition for neurones (glucose-lactate shuttle)
- Remove neurotransmitters (uptake) control concentrations
- maintain ionic environment around neurones e.g. K+ buffering
- help form blood brain barrier
Describe how the glucose- lactate shuttle is used by astrocytes
Neurones can’t store glycogen so astrocytes convert glycogen to lactate which can by used by neurones to produce Pyruvate for energy
This is called the glucose lactate shuttle as glucose transported into astrocytes and becomes glycogen then lactate transported into neurone
Why is it important for astrocytes to remove neurotransmitters through re-uptake?
Astrocytes have transporters for transmitters such as glutamate
This helps to keep the extracellular concentration low
Prevents excitotoxicity (too much Ca in post-synaptic cells -> activates destructive enzymes -> death)
Also means neurone can respond again
How do astrocytes help to buffer K+ levels in brain ECF and why is this necessary?
Astrocytes have a very negative resting potential - inward movement of K+ from the ECF into astrocytes though NaKCL2, Na K exchanger, K channels
High levels of neuronal activity -> rise in K+ in ECF -> neurones to have uncontrolled depolarisation
In depth role of microglia
Smallest glial cells
Immunocompetent cells (like macrophages for the brain)
Recognise foreign material -> activated -> thicker -> mature -> phagocytise debris/ foreign material/ plaques + APCs to T cells
Brain’s main defence system
What makes up the blood brain barrier?
Brain capillaries have:
- Tight junctions between endothelial cells
- basement membrane surrounding capillary
- end feet of astrocytes processes (helps to create the tight junctions)
What is the function of the blood brain barrier?
Limits diffusion of substances from blood to brain ECf
Maintains correct environment for neurones
-Lipid soluble molecules (O2/ CO2) freely move through membrane
- small ions normally could (glucose/ AAs/ K+) transported across due to tight junctions
REGULATED
What does it mean when we say the CNS is immune specialised or immune privileged?
Does not undergo rapid rejection of allografts bc CNS inhibits the initiation of pro- inflammatory T-cell response
Rigid skull so need to avoid inflammation - migroglia APCs to T-cells which can enter CNS
What are the three types of communication neurones can use across the synapse?
- fast excitatory neurotransmitters
- fast inhibitory neurotransmitters
- modulatory response
What does the response of neurotransmitters binding to post synaptic receptors depend on?
- nature of neurotransmitter
- nature of receptor (ligand gated ion channel/ G protein coupled)
What chemical classes can CNS neurotransmitters be divided into? Give examples of each category
- amino acids (glutamate, GABA, glycine)
- biogenic amines (acetylcholine, noradrenalin, dopamine, serotonin, histamine)
- peptides (dynorphin, enkephalins, substance P, somatostatin, cholecystokinin, neuroleptic Y)
What are the main CNS neurotransmitters? What about main excitatory and main inhibitory?
Over 70% of alll CNS synapses are glutamatergic throughout CNS
Main excitatory = glutamate as mostly excitatory
Main inhibitory = GABA (in brain) and glycine (Brainstem and spinal cord)
All three amino acid neurotransmitters
What are the two categories of glutamate receptors? What does activation of these cause? What receptors are in these categories and what are they permeable to?
- Inotropic (integral ion channel associated) - 3 types:
AMPA (Na/ K)*
NMDA (Na/ K/ Ca)*
*main ones at synapses, fast excitatory neurotransmitter response
Kainate (Na/K)
Activation causes depolarisation and increased excitability)
-metabotropic (g protein coupled receptor) - 1 type:
mGluR1-7
linked to either changes in IP3 and Ca2+ mobilisation OR inhibition of adenylate cyclase and decreased cAMP levels
How does the fast excitatory response work?
Excitatory neurotransmitters cause depolarisation of the postsynaptic cell by acting on ligand gated-ion channels causing an excitatory postsynaptic potential -> depolarisation causes more action potentials if reaches threshold
How do glutamatergic synapses work?
Have both AMPA and NMDA receptors
AMPA receptors mediate initial fast depolarisation - mg2+ sits in NMDA receptor pores and blocks. Activation of lots of AMPA causes depolarisation around receptors which pushes Mg out and opens channels
NMDA receptors are permeable to Ca2+ - need glutamate to bind and the cell to be depolarised to allow ion flow through the channel (glycine acts as a co-agonist)
How does learning and memory work at the synapse level?
Glutamate receptors important role
- activation NMDA receptors can up-regulate AMPA receptors -> strong high frequency stimulation causes long term potentiation (strengthening of synapses)
Ca entry through NMDA important role - different levels of ca determines if synapses has long term potentiation or long term depression (pruning)
How does a stroke spread damage in the brain?
Some cells die off and real ease potassium so K concentration increases this causes a spread of depolarisation -> activation neurones -> release glutamate = excitotoxicity
How do GABA and glycine receptors work?
GABAa and glycine receptors Have integral Cl- channels - opening causes hyper-polarisation -> inhibitory post-synaptic potential (decreased AP firing)
- some GABA (GABAb) have a Modulatory role
How do barbiturates and benzodiazepines work?
Both bind to GABAa receptors and both enhance the response to GABA
- barbiturates anxiolytic and sedative actions but risk of fatal overdose/ dependence/ tolerance increase. Now sometimes used as anti-epileptic drugs only
- benzodiazepines sedative and anxiolytic effects used for anxiety, insomnia, epilepsy
What do inhibitory interneurones in the spinal cord realease?
Glycine
Explain the knee jerk reflex
- Hit under patellar
- Stretch receptors in muscle spindle activate glutamatergic neurones
- Excitatory response on motor neurone from spinal cord
- Ach released from motor neurone to cause muscle contraction of hamstrings
- Sensory neurone also activates inhibitory neurone which is glycernergic so glycine released on motor neurone so contraction of quadriceps doesn’t occur
Which class of transmitters are mostly neuromodulators? Give examples
Biogenic amines e.g. acetylcholine, dopamine, noradrenaline, serotonin
Confined to specific pathways
Describe acetylcholine as a neurotransmitter
At the neuromuscular junction, ganglion synapse in ANS, postganglionic in parasympathetic only
Also a central neurotransmitter acts as both nicotinic and muscurinic receptors in the brain, mainly excitatory, receptors often present on presynaptic terminals to enhance release of other transmitters e.g. glutametergic neurones
Describe important cholinergic pathways in the CNS
Neurones originate in basal forebrain and Brainstem e.g. nucleus basalis
Give diffuse projections to many parts of cortex and hippocampus e.g. NB projections via septohippocampal pathway to hippocampus (arousal and learning)
Also local cholinergic interneurones e.g. in corpus striatum
Why do cholinesterase inhibitors help alleviate symptoms of Alzheimer’s disease?
The septohippocampal pathway (from nucleus basalis to hippocampus) is involved with arousal, memory, motor control and learning. It’s one of the first areas to degenerate in Alzheimer’s.
These use Ach as a neurotransmitter so increasing Ach in the synapse increases activation of neurones
Describe the dopaminergic pathways in the CNS and how some of these structures are involved in conditions and how they CNS be treated
Striatal interneurones/ corpus striatum connect to substania nigra = nigrostriatal pathway - involved in motor control
❌ Parkinson’s disease associated loss dopaminergic neurones (SN to CS)
✅ levodopa (converted to dopamine by AADC/ aromatic amino acid decarboxylase)
From Hippocampus to cortex = mesocortical pathway
From hippocampus to amygdala = mesolimbic pathway
- both involved in mood, arousal and reward
❌schizophrenia - May be due to release too much dopamine, antipsychotic drugs are antagonists to dopamine D2 receptors
Levodopa can be given as dopamine therapy to help treat Parkinson’s disease but too much dopamine in the peripheral nervous system causes side effects so how is this prevented?
Levodopa is converted to dopamine by AADC
Carbidopa inhibits AADC but can’t cross the blood brain barrier so prevents production of dopamine in the peripheral nervous system only to avoid GI side effects
Levodopa and carbidopa are therefore given in conjunction to treat Parkinson’s
What roles does noradrenaline play?
Transmitter at postganglionic - effect synapse in ANS
Also acts as neurotransmitter in CNS
Operates through G protein coupled alpha and beta adrenoceptors
Receptors to noradrenaline in brain are the same as in the periphery
Describe the noradrenergic pathways in the CNS. How are these lathways used by a drug? Also which condition may be associated with these pathways?
Cell bodies of noradrenergic neurones are located in Brainstem (pons and medulla)
neurones project into cortex/ cerebellum/ amygdala/ hypothalamus so diffuse release of NA
A single neurone has loads of synaptic endings
Most NA in brain comes from group of neurones in locus cereleus
- inactive during sleep
- increased activity in behavioural arousal
Amphetamines increase release of NA and dopamine and increase wakefulness
Relationship between mood and state of arousal
- depression may be associated with defiance of NA (and serotonin)
Describe serotonergic pathways in CNS
Serotonin, 5-HT similar distribution to NA neurones
Raphe nucleus contains many serotonergic neurones projects to cortex/ amygdala/ cerebellum/ hippocampus
Functions: sleep/ wakefulness and mood
SSRIS ✅depression ✅anxiety
