ELM22: Neuropathology Flashcards
What are synaptopathies?
Brain disorders caused by synaptic dysfunction
What are the three different mechanisms of synaptopathies?
Alterations in NT synthesis of release
Alterations in pre-synaptic vesicle machinery
Alterations in signalling expression and function of post synaptic NT receptors
What effect does LTP have on dendritic spine size?
Increased spine size
What effect does LTD on dendritic spine size?
Decreased spine size
What does dendritic spine size effect?
Post synaptic density
Number of glutamate receptors
Synaptic strength
What can occur in the brain due to morphological changes in dendritic spines?
Cognitive alterations
Neuropyschiatric disease
What are some causes of synaptopathies?
Genetics
Drug use
Aging
Viral infections
What can synaptopathies lead to?
Abnormal dendritic spine density and morphology
Synapse loss
Neuronal death
Aberrant synaptic signalling and plasticity
What is thought to be the cause of epilepsy?
Imbalance of excitatory and inhibitory circuits
What is thought to be the mechanism resulting in epileptic seizures?
- Enhanced glutamatergic neurotransmission and decreased GABA release
- Increase in excitatory neurotransmission
- Seizure episodes
What is Levetiracetam as a treatment for epilepsy?
Reduces NT release at glutaminergic synapses
What is Valproate as a treatment for epilepsy?
Increased amount of inhibitory GABA
What is Phenytoin as a treatment for epilepsy?
Prolongs Na+ channel inactivation
What are channelopathies?
Group of disorders caused by dysfunction of ion channels
How can channelopathies cause convulsions?
- Abnormal calcium and potassium channels in the brain
- Repolarisation defects
- Convulsions
What is GRIN2B?
Gene encoding NR2B
NR2B is involved in glutamate binding
What occurs due to a gain of function mutation in GRIN2B?
Hyperexcitability
Causes seizures
What occurs due to a loss of function mutation in GRIN2B?
Hypoexcitability
Causes learning difficulties and neurodevelopmental problems
What are the three main types of glia in the brain?
Astrocytes
Microglia
Oligodendrocytes
What is the function of astrocytes?
Structural
Metabolic sensing
Repair and modulation synapse transmission
What is astrocyte reactivity?
Hypertrophy and proliferation
Caused neuroprotection
What is astrodegeneration?
Atrophy and functional asthenia
Causes neurotoxicity
What is the function of microglia?
Immune defence of the CNS
What is the nurturer state of microglia?
Highly ramified and evenly spaced
Maintain milieu homeostasis
Synaptic remodelling and migration
Remove apoptotic neurons
What is the sentinel state of microglia?
Abundant processes In motion Surveillance and sensing
What is the warrior state of microglia?
Stocky and less ramified
Defence against pathogens and injurious self proteins
How can microglia cause further neurodegeneration?
- Disease stimulus
- Sensing and host defence
- Dysregulation due to host defence
- Exaggerated proinflammatory response and neurodegeneration
What is the function oligodendrocytes?
Formation of myelin
What are the symptoms of multiple sclerosis?
Limb numbness and weakness Electric shock sensations
Tremor
Fatigue and dizziness
What is the cause of neuroinflammation in encephalitis and MS?
Invading immune cells
What is the cause of neuroinflammation in neurodegenerative processes?
CNS resident cells
What are four features of neuroinflammation?
- Increased production of cytokines and reactive oxygen species
- Molecular rearrangement of postsynaptic glutamate receptors
- Impairment of hippocampal LTP
- Axonal and dendritic loss
What is the blood brain barrier?
Continuous endothelial membrane of the brain vasaculature
What is the function of the blood brain barrier?
Separate circulating blood and brain compartments
Regulate blood to brain
What is needed for delivery of drugs?
Healthy blood vessels
Normal formation of blood vessels
Adequate blood flow
Recruitment of active transport systems
How does the breakdown of the blood brain barrier promote 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
What are the features of blood brain barrier disruption in alzheimers disease?
Brain capillary leakages
Pericyte degeneration
Endothelial degeneration
Cellular infiltration
What are the features of blood brain barrier disruption in parkinsons disease?
Brain capillary leakages
Endothelial degeneration
Cellular infiltration
What are the features of BBB disruption in huntingdons disease?
Brain capillary leakages
Endothelial degeneration
What are the features of BBB disruption in MS?
Brain capillary leakages
Endothelial degeneration
Cellular infiltration
What are some causes of impaired drug delivery when the BBB breaks down?
Impaired solute transport
Diminished ISF regional flow
Decreased function and AT systems
Drugs trapped in enlarged perivascular spaces
