Neuropathologies Flashcards
What is a synaptopathy?
brain disorders that have arisen from synaptic function
How does a synapse work?
- Action potential arrives
- Opening of voltage-gated calcium channels
- Vesicle fusion
- Neurotransmitter release
- Postsynaptic events
What are the different synaptopathy mechanisms?
a) Alterations in neurotransmitter synthesis or release
b) Alterations in pre-synaptic vesicle machinery
c) Alterations in signalling, expression and function of postsynaptic neurotransmitter receptors
What forms synapses with other neurones?
Dendritic spines
What can long term potentiation and depression lead to in terms of dendritic spines?
- Long term potentiation (LTP) can lead to increased spine size
- Long term depression (LTD) can lead to decreased spine size
What does spine size correlate with and what is it linked to??
Spine size correlates with postsynaptic density, number of glutamate receptors and synaptic strength, and is linked to synaptic plasticity, learning and memory
What dendritic spine morphological changes do you see with cocaine addiction and Alzheimer’s disease?
- Cocaine addiction: bigger, mature spines
- Alzheimer’s disease/ mental retardation: thinner, immature spines
What do synaptopathies result from?
- Genetics
- Drug use
- Ageing
- Viral infections
What do synoptapathies lead to?
- Abnormal density and morphology of dendritic spines
- Aberrant synaptic signalling and plasticity
- Synapse loss
- Neuronal death
What is epilepsy characterised by and what increases the susceptibility of getting it?
- Cause unknown
- Affects around 50 million people worldwide
- Characterised by the occurrence of epileptic seizures which are uncontrolled and excessive synchronised electrical activity of central neurons
- Cause unknown but infection, stroke and traumatic brain injury increase the susceptibility of developing epilepsy
What is the hypothesis about epilepsy?
- Thought to be caused by an imbalance of excitatory and inhibitory circuits
- Glutamatergic neurotransmission is enhanced, while GABA release is decreased
- So overall increase in excitatory neurotransmission
What are current treatments for Epilepsy?
- Current treatment includes anti-convulsant and anti-epileptics
- Levetiracetam reduces neurotransmitter release at glutamatergic synapses
- Valproate increases amount of inhibitory GABA
- Phenytoin prolongs inactivation of Na+ channels
In inherited epilepsy what can many of the genetic causes be traced to?
A mutation in an ion channel such as the GABAA receptor, voltage-gated potassium channels, voltage-gated sodium channels, chloride channels and neuronal nicotinic acetylcholine receptors
What are ion channels?
proteins that span across the cell membrane allowing passage of ions from one side of the membrane to the other
What do voltage gated channels and ligand gated channels open in response to?
- Voltage gated channels: opens in response to change in the membrane potential
- Ligand-gated channels: opens in response to a specific extracellular neurotransmitter
What do ions play critical roles in?
Controlling neuronal excitability
What are channelopathies and what can they lead to?
- Channelopathies are a group of disorders resulting from the dysfunction of ion channels; usually from genetic or autoimmune origin
- Channelopathies can lead to different types of epilepsy, migraine, ataxia an paralysis
What can abnormal K+ and Ca2+ channels in the brain lead to?
Abnormal K+ and Ca2+ channels in the brain -> repolarisation defects -> convulsions (epilepsy)
What are GRIN2B mutations and what do they lead to?
- Mutations in GRIN2B, the gene encoding NR2B, the beta-2 subunit of the NMDA receptor, which is a ligand-gated ion channel that binds to glutamate
- Gain of function -> hyperexcitability -> seizures
- Loss of function -> hypo excitability -> learning difficulties and neurodevelopmental problems (as there are not enough connections in the brain)
What is Myotonia congenita?
- The goats’ muscles are sometimes unable to relax after they’ve contracted, causing the goats to keel over
- This is caused by a mutation in the skeletal muscle chloride channel, CLCN1 and can be triggered when the animals are startled or excited
What is malignant hyperthermia and what does it cause?
- Malignant hyperthermia is a condition that occurs in attacks, in response to specific triggers
- It involves a state of hyperactivity in muscle cells due to excessive release of calcium from the sarcoplasmic reticulum. This causes the muscles to contract and become rigid and cause a high fever. It can also cause a very fast heart rate
- If untreated it can cause rhabdomyolysis (muscle breakdown) and very high blood potassium levels which can be fatal.
How do most people live with malignant hyperthermia, what are some of the triggers and what is it most commonly caused by?
- Most people are able to lead a normal life if they avoid the triggers
- One of the most common triggers is general anaesthesia but some people can also experience an attack if they become very hot due to exercise.
- Malignant hyperthermia is most commonly caused by a mutation in the ryanodine receptor (a sarcoplasmic reticulum calcium channel)
What are some pathological changes to astrocytes that take place after traumatic brain injury or a stroke?
Astrological reactivity: hypertrophy and proliferation (bigger and more of them) – neuroprotection
What are some pathological changes that take place to astrocytes with Alzheimer’s disease, Huntington’s disease, schizophrenia and major depressive disorders?
Astrodegeneration: atrophy and functional aethenia – neurotoxicity
What are the three functional states of microglia?
- Nurturer
- Sentinel
- Warrior
What are Microglia in their nurturer state?
- Highly ramified and evenly spaced
- Maintain milleu homeostasis
- Synaptic remodelling and migration
- Removal of apoptotic neurones
What are features of microglia in their sentient state
- Abundant processes and in motion
- Surveillance and sensing
What are features of microglia in their warrior state?
- Stocky and less ramified; they accumulate
- Defence against infectious pathogens and injurious self-proteins
What are effectors of microglia function associated with and how does this work?
- Disease stimulus
Tau (dementia)
HTT (Huntington’s) - Proteins disrupts microglial housekeeping functions
- Exaggerated proinflammatory response, Neurotoxicity, Neurodegeneration
What is multiple sclerosis caused by?
A loss of myelin
What does a loss of myelin in the brain and spinal cord lead to?
impairment of axonal conductance and nerve damage
What are some symptoms of multiple sclerosis?
- Limb
- Numbness/weakness
- Electric-shock sensations
- Tremor
- Vision problems
- Fatigue, dizziness
- There is no cure, but treatment can help manage symptoms
In encephalitis and MS how is inflammation caused?
- Demyelinating disease or encephalitis
- Leukocyte invasion of CNS parenchyma
- Cytokine production by lymphocytes and myeloid cells
- Tissue damage
How is inflammation triggered in neurodegenerative processes such as AD and PD?
triggered by CNS-resident cells
- Homeostatic imbalance/ toxin protein aggregates
- Activation of stromal cells and microglia
- Cytokine
What are neuroinflammation events?
- Increased production of cytokines and reactive oxygen species (ROS)
- Molecular rearrangement of postsynaptic glutamate receptors
- Impairment of hippocampal LTP
- Axonal and dendritic loss
How are the endothelial cells that line the capillaries joined together in the brain?
joined together by tight junctions which restrict the movement of solutes and the migration of cells and pathogens into the brain.
What are endothelial cells surrounded by in the brain and what is needed in order to move substances across the blood-brain barrier?
The endothelial cells are surrounded by pericytes and the astrocytic ‘feet’. These are projections of astrocytes that are associated with the capillaries. In order to move substances across the blood-brain barrier, active transport is needed
Why is the blood brain barrier beneficial?
it protects the brain from infections that are happening in the periphery
What is a problem with the blood bran barrier?
it excludes many drugs from the brain which can make it difficult to target brain disorders
What is the main function of the blood brain barrier?
to separate the circulating blood and brain compartments and regulate blood-to-brain and brain-to-blood transport of solutes
What does the delivery of blood through the blood brain barrier require?
Healthy blood vessels
Normal formation of blood vessels
Adequate blood flow
Recruitment of active transport systems (e.g. CMT or RMT)
What does the breakdown of the blood brain barrier promote and why?
• Blood brain barrier breakdown promotes neurodegeneration
- Increased vascular permeability
- Toxic blood-derived molecules, cells and microbial agents enter brain
- Inflammatory and immune responses
- Neuronal injury, synaptic dysfunction, loss of neurons, loss of brain connectivity, neurodegeneration
Why is delivery of drug to the brain impaired when the blood brain barrier breaks down?
- Impaired solute transport
- Diminished ISF (interstitial fluid) regional flow
- Decreased function of active transport systems
- Drugs can get trapped in enlarged perivascular spaces
