NEURONS Excitable cells Therefore, have a RMP Synapse = chemical communication site between neurons, from pre-synaptic release to postsynaptic

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1 NEUROPHYSIOLOGY NOTES L1 WHAT IS NEUROPHYSIOLOGY? NEURONS Excitable cells Therefore, have a RMP Synapse = chemical communication site between neurons, from pre-synaptic release to postsynaptic receptor Neurons are classified as excitatory or inhibitory depending on whether they increase or decrease post-synaptic neuronal activity respectively L2 GLIAL CELLS Glial cells refer to all cells in the NS other than neurons. This includes: Oligodendrocytes/Schwann Cells Ependymal cells Astrocytes Microglia Satellite Cells Glial Cell Name Oligodendrocytes and Schwann Cells Function Make myelin, which wraps around axons to increase conduction velocity Oligodendrocytes are found in the CNS Schwann Cells are found in the PNS Microglia Brain s immune system Survey the brain for invasion and damage, and respond Macrophage lineage Satellite Cells Support neurons in ganglia Found in the PNS Ependymal Cells Line ventricles and surfaces of the brain Form barriers between neuronal compartments Ensures soluble factors in the NS stay compartmentalised Source of neuronal stem cells ASTROCYTES

2 Functions of Astrocytes Support cells in the CNS Maintain a stable environment for the NS and neurons Helps form the blood brain barrier o Astrocytes interact with endothelial cells of blood vessels o Allows selective entry of products into the brain, helping to maintain a relatively constant environment o e.g. limits entry of glutamate, preventing a mass excitatory response in the brain Secretes neurotropic factors, which support neurons Take up K+ and neurotransmitter The number of astrocytes per neuron in the NS increases with increased NS complexity. Where are Astrocytes found? Fill up all spaces between neurons that are not synapses Found everywhere that synapses are not Astrocyte Territory Astrocytes have their own territory Territories have very small overlap An astrocytes territory is the region of the brain which they maintain Siphon Processes of Astrocytes The siphon process projects out of the cell body, towards a nearby blood vessel, attaching to the blood vessel à forms the blood brain barrier Siphon process has a role in determining blood flow o Increased astrocyte function leads to an increased glucose requirement o This then causes reactive hyperaemia à blood flow increases to active areas of the brain and decreases to inactive areas of the brain o fmri can be used to record this change in blood flow Astrocyte Function around Synapses Astrocytes surround synapses They separate different synapses, preventing NT from one synapse affecting the post-synaptic cell of another synapse They maintain the fidelity of information transfer across a specific synapse The tripartite synapse includes the pre-synaptic neuron, the post-synaptic neuron and astrocytes

3 Astrocyte Ion Uptake APs in neurons result in K+ moving out of the cell and into ECF, therefore, there is potential for ECF [K+] to increase Increased ECF [K+] will cause RMP to increase, and neurons will be more likely to fire APs Astrocytes take up extra K+ in ECF to maintain a constant ECF [K+], and hence maintain the neurons environment and excitability Mechanisms of K+ Uptake in Astrocytes utilise active transport, co-transporters and channels, and include: o Na+/K+ ATPase o Na+/K+ symporter o Other transporters/channels which support the action of the above transporters include Na+/H+ exchanger, Na+/HCO3- cotransporter (electrogenic pump unique to glial cells), Cl- /HCO3- exchanger Spatial Buffering Once astrocytes take up a high concentration of ions (e.g. Ca2+, K+), they distribute the absorbed ions amongst their culture This occurs via gap junctions between neighbouring astrocytes K+ moves from an astrocyte with a high ICF [K+] to one with a low ICF [K+] Gap Junctions

4 Connexin Connexon Gap Junction Transmembrane protein with 4 transmembrane domains Comprised of 6 connexins Form a pore in the middle Comprised of 2 connexons Form when connexons of adjacent astrocytes line up Properties of Gap Junctions: Cells can increase/decrease conductance through gap junctions, and hence they can be modulated Pore of gap junctions excludes movement of particles on the basis of size (small particles can move through, but large particles cannot) K+ can easily move through gap junctions Movement of particles through a gap junction is bidirectional Ions carrying a current that move through a gap junction will carry the current through the gap junction (depolarisation of one cell will cause depolarisation of adjacent cells joined by gap junctions) Responsive Astrocytes Activation of neighbouring astrocytes can also be a result of NT release Astrocytes have receptors to react to NTs This allows astrocytes neighbouring a synapse where NT has been release to be affected, and in turn affect other close by synapses Glutamate stimulates astrocytes causing an intracellular Ca2+ response: o Stimulation of an astrocyte triggers a GPCR o This initiates a Ca2+ response via IP 3 o Via gap junctions, Ca2+ moves into adjacent astrocytes, causing a Ca2+ response via IP 3 etc.

5 Reactive Astrocytes Introducing a physical barrier between astrocytes doesn t affect the spreading of the Ca2+ response, it only takes a longer time This shows that gap junctions aren t the only form of communication in astrocytes Astrocytes can communicate by releasing signalling substances into ECF ATP can be released in response to Ca2+, triggering a Ca2+ response in nearby, but not physically connected astrocytes Astrocytes can release NT as well, by putting NT into vesicles, and then releasing this NT into the ECF to affect a neuron or astrocyte The neuroactive substances that glia release are termed gliotransmitters Astrocytes can release glutamate to: o Feedforward to the post-synaptic neuron and increase responsivity o Feedback to the presynaptic neuron SUMMARY OF ASTROCYTE FUNCTION L3 RESTING MEMBRANE POTENTIAL

6 RMP Difference in voltage/potential across the membrane of an excitable cell at rest RMP = -65mV in a neuron Changes in potential from RMP (depolarisation or hyperpolarisation) allow cells to pass on information ION CONCENTRATIONS IN ICF AND ECF These concentration gradients, and a resting permeability to K+ establish RMP. Ion ICF (mm) ECF (mm) K ICF>ECF Na ECF>ICF Cl ECF>ICF Ca ECF>ICF ION TRANSPORTERS AND EXCHANGERS Ion transporters and ionic exchangers are important in establishing ion concentration gradients. Ion transporters and exchangers allow for unidirectional movement of ions across the cell membrane. Ion Transporters Pumps which use energy Drive ions against their concentration gradients Involved in creating ion concentration gradients ATPase pumps include Na+/K+ ATPase and Ca2+ ATPase Na+/K+ ATPase Responsible for establishing and maintain the concentration gradients of Na+ and K+ Binds 3Na+, and transports them from ICFàECF Binds 2K+, and transports them from ECFàICF Creates a net negative charge inside the cell, therefore it is an electrogenic pump α subunit is important for its ATPase function β subunit is important for its transporter function Transmembrane spanning protein

7 When Na+ and K+ bind, a conformational change is induced, resulting in Na+ and K+ being moved across the membrane Intracellular binding site for ATP Ouabain binding site, which acts as a modulator of activity Ionic Exchangers Don t directly use energy Use the potential which arises from concentration gradients to exchange ions K+ MOVEMENT AT RMP K+ concentration gradient is equally opposed by an electrical gradient as the cells RMP is equal to K+ equilibrium potential So despite the cell being permeable to K+, there is no K+ movement CAPACITANCE Cell membrane is very thin, so opposing charges on either side of the membrane attract each other The cell membrane is relatively more positive on the outside and relatively more negative on the inside This results in ion flux not drastically changing the overall charge of ICF or ECF, because a relatively small amount of ions move across the membrane However, this is enough to cause a change in MP and initiate an AP ION CHANNELS Ion channels are a pore in the cell membrane The structure of ion channels does not have any characteristics which determine the direction of ion movement Ion channels are bidirectional and ion movement across the membrane through a channel will depend on concentration gradients Ion Selectivity through Ion Channels Size is thought to contribute to selectivity of ion channels for certain ions, but there aren t large differences in the size of ions K+ ion channel is composed of 4 subunits, which is open at RMP, and allow movement of K+ down its concentration gradient When K+ is on either side of the channel, K+ is hydrated, but when inside the channel K+ is unhydrated

8 Unhydrated K+ perfectly interacts with the R groups of amino acids which line the pore, perfectly mimicking the low energy hydrated state This pattern of bonding is the selectivity filter of the channel A small change in the arrangement of the channel, makes binding inside the pore energetically unfavourable Na+, Cl- or Ca2+ binding inside the K+ channel is energetically unfavourable and so doesn t happen GATING Gating is the opening and closing of ion channels Different determinants of gating include: o Voltage gated ion channels = MP changes lead to the channel opening or closing o Ligand gated ion channels = ligand binding leads to the channel opening or closing o Mechanically gated ion channels = motion or deformation leads to the channel opening or closing Gating typically occurs by a conformational change occurring about a gating hinge EXAMPLES OF ION CHANNELS TYPES OF K+ CHANNELS

9 Inward rectifier and K+ 2 pore channels have characteristics which enable them to contribute to RMP à that is, they re open at RMP Experiment where different K+ ion channels have their current measured while being depolarised, hyperpolarised and at rest: