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Physiology and pharmacology of CNS lecture notes
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Physiology of CNS lecture notesLecture 2 – synapses
MEPPs – miniature end plate potential which are due to random release of neurotransmitter, usually
from a single vesicle.
EPSPs and IPSPs are subthreshold events, which add up to determine whether a neuron will fire an
action potential. They can cancel each other out. Made up of miniature end plate potential.
EPSPs (excitatory post synaptic potentials) add up to cause depolarization
IPSPs (inhibitory post synaptic potentials) add up to cause hyperpolarization
Total activity in the cell body determines if the cell fires an action potential. Further away the
dendrite the less effect it will have.
Syntaxin I – t snare, open confirmation which is the active form. Closed confirmation binds munc18
which allows it to convert to the open confirmation and allows interaction with snap 25. Snare
motifs line up.
Synaptobrevin - v snare
Snap 25 – t snare
Complexin clamp – docking but no fusion at this stage.
Synaptotagmin – calcium sensor. C2B binds 2 calcium, C2A binds 3 calcium, each synaptotagramin
have 10 protons. Binds syntaxin I, removes complexin clamp, promotes vesicle fusion, bends
membrane phospholipids.
Botulinum and tetanus toxin interact with the snare complexes at the snare motifs to prevent vesicle
release
NSF binds snap, ATP is hydrolyzed to ADP + Pi, energy is released to break the cis snare complex, the
t snares are taken up by endocytosis.
What is spatial summation – subthreshold events occur at different spines at the same time
What is temporal summation - Temporal summation occurs when subthreshold events occur at the
same dendritic spine in a close amount of time
Summation occurs at the axon hillock, size of input decreases as it travels to the axon of hillock
Axon of hillock contains many sodium and potassium channels
,L3 - Intro to glia
Two major classes of cells in the brain:
Neurons – electrically excitable
Glia – electrically non-excitable, unable to generate action potentials, but express voltage gated
channels, not vascular cells, homeostatic cells of the brain.
Two types of glia:
1. macroglia has a neural ectodermal origin – astroglia, oligodendroglia, NG2-glia
2. microglia has a non-neural mesodermal origin – originate from macrophages which invade the
brain during fetal development
Peripheral glia – Schwann cells, satellite cells of sensory and sympathetic ganglia, olfactory
ensheathing cell and enteric glia
Astrocytes – classical star like morphology (protoplasmic, fibrous), express intermediate filaments
such as GFAP, can form processes under the surface of pia matter (glial limitans) and can extend to
contact nodes of Ranvier of myelinated axons. Processes also enwrap capillaries in BBB. Single
astrocyte contacts multiple dendrites of a single neuron. Single neurons are associated with multiple
astrocytes. Usually no overlapping between astrocytes
Oligodendrocytes – not many functions, myelinate 30-50 neuronal axons within 20-30 microM of the
cell body (soma)
NG2 glia – express neuron-antigen-2 or chondroitin sulphate proteoglycan, they are thought to
derive from oligodendrocyte precursor cells, form contacts including synapses with neurons in grey
matter, characterized as having a small soma and numerous thin processes. They can generate
oligodendrocytes during developmental remodeling, may serve as multipotent adult stem cells.
Microglia – mesodermal origin, form the brain immune system, appear in 3 states. Resting, active
and phagocytic.
Schwann cells – myelinating and non-myelinating (have similar functions to astrocytes, include peri
synaptic Schwann cells which ensheath terminal axon branches and synaptic boutons at the
neuromuscular junction). Can differentiate and dedifferentiate which can differentiate to myelinated
or non-myelinated, supports nerve regeneration of peripheral nerves.
Cell signaling – chemical, electrical synapses connect via transcellular channels each formed by 2
connexons
Tripartite synapse – consists of presynaptic terminal, post synaptic membrane and surrounding
astrocyte process, which contribute to the activity of the synapse. Calcium triggers the release of
,neurotransmitters and glial transmitters. Receptors on each component match to optimize local cell
to cell communication.
Glial cell receptors – ionotropic and metabotropic
Volume transmission – slow, exhibits one to many transmissions via diffusion
Wiring transmission – via chemical synapses or electrical synapses, it is rapid and 1:1
Astrocytes physiological properties
1. do not fire action potentials but respond to neurotransmitter and blood hormones, use calcium
ions for signaling, activation of 1 astrocyte cell via neurotransmitter will spread the signal across
other astrocytes.
Inter-glial calcium waves – maintained by diffusion of a second messenger through gap junctions, or
by calcium dependent release of glial transmitter such as ATP and glutamate, which act on
neighboring cells through extracellular diffusion, or extracellular volume transmission
Gliotransmitters – Glutamate, ATP, D-serine, can bind to respective receptors on neurons to
modulate firing frequency and synaptic transmission
Glial cells also release peptides such as NPY.
Function of glia:
astrocytes
1. support
2- homeostasis –
K+ buffering, have a high K+ resting conductance and a very negative resting membrane potential,
form a syncytium of cells connected by gap junctions. Local K+ uptake occurs in individual cells via
inwardly rectifying K+ channels which depolarizes the cell to stop K+ influx, but K+ is moved across
neighboring cells through gap junctions so prevents depolarization and maintains K+ influx. K+ are
removed from the astrocyte and transported into perivascular system or the interstitium. Rectifying
channels allow both inward and outward movement of K+ ions which is completely governed by its
concentration.
water regulation, regulates local shrinkage due to neurotransmitter release, water accumulates at
places with high neuronal activity. Water is taken up by aquaporin 4 colocalized with K+ inwardly
rectifying channels.
extracellular pH, neuronal activity releases carbon dioxide which reacts with water to produce
protons, which is neutralized by bicarbonate
3. maintenance of blood brain barrier properties
4. astrocyte-neuronal lactate shuttle, to provide energy for active neurons, glucose is taken up by
GLUT-1 and converted to lactate. Lactate is taken up by neurons via monocarboxylic acid
transporters (MCT).
, 5. regulation of cerebral blood flow
6. astrocyte injury response
Oligodendrocyte – myelinate axons in the CNS
Microglia – resting microglia scan brain territory and is suppressed by presence of
neurotransmitters. Active microglia due to trauma aim to destroy foreign cells, phagocytic microglia
remove damaged cells and debris.
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