Neuropathology

• SYNAPTOPATHIES

  • disorder where there is disfuction in one of the various components of the synapse
  • arisen from synaptic dysfunction
  • HOW SYNAPTOPATHIES WORK

  1. alternation in neurotransmiter synthesis and release
  2. alternations in pre0synaptic vesicle machinery
  3. alternations in signalling expression and function of post-synaptic neurotransmitter receptors
• CHANGES IN DENDRITIC SPINES AFFECT SYNAPTIC FUNCTION:

  • long term potentiation--> to increased spine sizes
  • Long term depression --> decreased spine size
  • spine size correlated with post synaptic density, number of glutamate receptors and synaptic strength --> linked to synaptic plasticity, learning + memory

  MORPHOLOGICAL CHANGES IN DENDRITIC SPINES:

  • cognitive alternation in neuropsychiatric disease
• CHANGES IN DENRITIC SPINES

  • CONSEQUENCES RESULT FROM:

  1. genetics
  2. drug use
  3. ageing
  4. viral infections

  • LEAD TO:

  1. abnormal density and morphology of denritic spines
  2. aberrant synaptic signalling and plasticity
  3. synapse loss
  4. neuronal death
• EPILEPSY

  • characterized by the occurrence of epileptic seizures --> uncontrolled and excessive synchronized electrical activity of central neurons
  • unknown cause --> but infection, stroke + traumatic brain injuries increases risk of developing epilepsy
  • thought to be inherited  traced to a mutation in ion channel
  • hypothesis

  1. is though to be caued by an imbalance of excitatory and inhibitory circuits
  2. glutamaterfic neurotransmitter is enhanced + gaba release is decreased
• EPILEPSY cont.

  • treatment

  1. anti-convuslsant and anti-epileptics
  2. levetiracetam --> reduces neurotransmitter release at glutamaterfic synapse
  3. valproate --> increases amount of inhibitory gaba
  4. phenytoin --> prolongs inactivation of sodium channels
• CHANNELOPATHETIES

  • ion channels --> protein molecules that span across the cell membrane allowing passage of ions from one side to another
  • voltage-gated and ligand-gated channels 
  • ion channels play a critical role in controlling neuronal excitability
  • channelopathies --> group of disorders resulting from the dysfunction of ion channels  genetic or autoimmune
  • lead to different types of epilepsy, migraine, ataxia and paralysis

  1. eg. abronal potassium and calcium levels in the brain --> repolarization defects --> epilepsy
• CHANNELOPATHETIES cont.

  • grin2b mutation

  1. gene encoding nr2b --> beta-2 subuunit of nmda receptor (ligand-gated ion channel that binds to glutamates)

  • myotonia congenita

  1. found in animals
  2. waiting goats
• CHANNELOPATHETIES cont.

  • malignant hyperthermia

  1. occurs in attacks in response to specific triggers
  2. state of hyperactivity in muscle cells due to excessive release of calcium from the sr
  3. cause mucles to contract and become rigid --> cause a high fever + very fast heart rate
  4. can cause rhabdomyolysis and very high potassium levels --> fatal
  5. common trigger --> general anaesthesai or if they become hot due to excericese 
  6. mutation in the ryanodine receptor
• GLIAL CELL PATHOLOGIES

  • 3 main types:

  1. astrocytes
  2. microglia
  3. oligodendrocytes
• ASTROCYTES

  • many functions --> structural, metabolic sensing, repair, modulation synapse transmission
  • can become reactive (undergo hypertrophy and proliferation) --> neuroprotection

  1. protective change aimed at the regeneration and proliferation of new tissues
  2. traumatic brain injury or stroke

  • astrodeenation (atrophy and functional asthenia) --> neurotoxicity

  1. found in patients with alzeimers, Huntingtons, schizophrenia, major depressive disorders
• MICROGLIA

  • main role --> active immune defence of the CNS
  • 3 states:

  1. NURTURER: highly ramified and evenly spaced/ maintained milieu homeostasis/ synaptic remodelling and migration/ removal of apoptotic neurons
  2. SENTINEL: abundant processes and in motion/ surveillance and seasoning
  3. WARRIOR: stocky and less ramified --> accumulate/ defence against infectious pathogens and injurious self proteins
• OLIDOGENDROCYTES

  • main function is formation of myelin --> key for high velocity nerve conduction
  • demyelinating --> multiple sclerosis --> degneration in autoimmune disease

  1. loss of myelin in the brain or spinal cord leads to an impairment of axonal conductance and nerve damage
  2. recovery can occur but replaces occur
  3. cause is unknown
  4. symptoms
• NEUROINFLAMMATION

  • in encephalitis and multiple sclerosis --> inflammation is caused by invading immune cells
  • in neurodegenetitive processes --> inflammation is triggered by CNS-resident cells
  • events

  1. increased production of cytokines and reactive oxygen species
  2. molecular arrangement of post-sysmpatic glutamate receptors
  3. impairment of hippocamapal ltp
  4. axonal and dendritic loss
• BLOOD BRAIN BARRIER

  • continuous endothelial membrane of brain vascularature
  • sealed cell-to-cell contracts
  • main function --> separate the circulating blood and brain compartments + regulate blood-to brain and brain-to-blood transport of solutes
  • Implications of drug delivery:

  1. requires healthy blood vessels
  2. requires normal formation of blood vessels
  3. requires adequate blood flow
  4. requires recruitment of active transport system
• BLOOD BRAIN BARRIER cont.

  • Implication of drug delivery when it b breaks down:

  1. impaired solute transport
  2. diminished its regional flow
  3. decreased function of active transport systems
  4. drugs can trapped in enlarged perivascular spaces

  • contains 644km of blood vessels

  1. supply brain cells with oxygen, energy metabolites and nutrients + remove carbon dioxide and other metabolic waste products from the brain
• BLOOD BRAIN BARRIER cont3.

  • blood brain barriers breakdown promote neurodegenerations

  1. increased vascular permeability
  2. toxic-blood-derived molecules + cells + microbial agonist enter the brain
  3. inflammatory and immune response
  4. neuronal injury, synaptic dysfunction, loss of neurons, loss of brain connectivity, neurodegenation