CSB332 Lecture 12 Notes

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University of Toronto St. George
Cell and Systems Biology
Francis Bambico

CSB332 Lecture 12 Slide 2 - What is common among these three situations in terms of activity in the brain (e.g., person suffering from anxiety or panic attack, person being attacked by a swarm of bees, child suffering from an epileptic seizure)? - These three conditions reflect hyperactivation of different regions of the brain. Hyperactivation results in dramatic increase in the release of neurotransmitters. There could be uncontrollable release of neurotransmitters in the synaptic cleft. But neurons and brains have built-in mechanisms under normal physiological conditions to control uncontrollable release of neurotransmitters in the synaptic cleft. Slide 3 - Neurotransmitter is released into the synaptic cleft. Neurotransmitters can activate three subtypes of receptors. o These receptors may be located on the postsynaptic cell (called postsynaptic receptors). o Neurotransmitters can stray from the synaptic region and activate extra-synaptic receptors located outside of the synaptic region, especially when there is a spill over or when there is an uncontrollable release of neurotransmitters. o Neurotransmitters can stay in the synaptic cleft and activate receptors that are located on the presynaptic neuron (called presynaptic autoreceptors). Autoreceptors meaning receptors for the self (e.g., self-receptors). Autoreceptors can be located on the presynaptic axon or somatic dendritic sites of the neuron (e.g., cell bodies, dendrites). Slide 4 - After activation and depolarization, neurons have built-in mechanisms to regulate further neurotransmitter release. - One mechanism is located on the postsynaptic cell. When neurotransmitters activate postsynaptic receptors, further postsynaptic activity is prevented by the activation of calcium- activated potassium channels. o The cholinergic receptor that is activated by acetylcholine. Ca2+ flows into the cell. The increased levels of Ca2+ concentration in the cell activate the calcium-activated potassium channel. o The calcium-activated potassium channel is permeable to K+. This leads to the efflux of K+, resulting in the hyperpolarization of postsynaptic cell, preventing further depolarization. - One subtype of calcium-activated potassium channel is called SK channel. SK channel is important in the termination of the action potential. o Recall that the action potential is generated after the decline in membrane potential. There is a period called afterhyperpolarization. Afterhyperpolarization switches the neuron into a refractory period. Afterhyperpolarization is caused by the activation of SK channels. o If you block SK channels, then you would have a continuous strain of action potentials. o The neurotoxic component of bee venom called apamin blocks calcium-activated potassium channels. One of the symptoms of being attacked by a swarm of bees is muscle paralysis resulting from spasms, disorientation, problems in heart function, and seizures. Slide 5 - This is another mechanism that regulates neurotransmitter release. - This is a sympathetic neuron releasing NE. NE binds to the α2-adrenergic receptor on its own presynaptic axon. Autoreceptors are typically coupled to an inhibitory G protein (Go or Gi). α2- adrenergic receptor is coupled to a Gi protein. When activated by NE, the beta and gamma subunits of the G protein will dissociate and will decrease the conductance of the Ca2+ channel. It will prevent the further influx of Ca2+ into presynaptic axon. The increase in the levels of presynaptic Ca2+ is responsible for exocytosis of neurotransmitters. The decrease in Ca2+ concentrations would lead to the prevention of further release of NE in synaptic cleft. Slide 6 - This is a third mechanism regulating neurotransmitter release. - This is different from presynaptic autoinhibition because it is caused by the release of neurotransmitter from presynaptic axon. - This mechanism is via retrograde messengers, which are molecules that are released by the postsynaptic back into synaptic cleft. When released, retrograde messengers activate presynaptic receptors that are inhibitory. An example of retrograde inhibitory molecules is endogenous cannabinoids, which are the brain’s cannabis-like ligand that activates cannabinoid CB1 and CB2 receptors in the CNS. - When the metabotropic and ionotropic receptors on the postsynaptic neuron are activated, it leads to the increase in Ca2+ concentration, leads to the synthesis of endogenous cannabinoids, leads to the enhanced release of endogenous cannabinoids into the synaptic cleft as retrograde messengers. Two examples of endocannabinoids are AEA and 2-AG. Once in the synaptic cleft, they activate cannabinoid CB1 or CB2 receptors. CB1 receptors are mainly located on the presynaptic axons of glutamatergic and GABAergic interneurons. These receptors are negatively coupled to adenylyl cyclase or Gi protein, which results in inhibitory action on the presynaptic axon. This results in decrease in Ca2+ influx and increase in Ca2+ efflux. This prevents further neurotransmitter release into synaptic cleft, thus preventing further activation of the postsynaptic neuron. This is what THC does. Slide 7 - When the effects are blocked by pertussis toxin, then that means that the activity of the cannabinoid receptor is operating by a Gi protein. Slide 8 - Endocannabinoids mediate two types of short-term synaptic plasticity. - DSI occurs in type 2 or inhibitory synapses. DSE occurs in type 1 or excitatory synapses. DSI and DSE refers to the process in which endocannabinoid release as retrograde messengers prevent further neurotransmitter release from the presynaptic axon, thereby inhibiting excitation or inhibition of the postsynaptic cell. - The CB1R is expressed on the presynaptic axon. The presynaptic axon is a GABAergic (e.g., inhibitory or type 2 synapse) interneuron. When the postsynaptic cell is activated by neighbouring excitatory inputs, the depolarization would result in the activation of enzymes (DAGL and PLCβ1) that would result in an increased synthesis of endocannabinoids (2-AG). 2-AG is synthesized in the postsynaptic cell on demand (e.g., in an activity dependent manner). The postsynaptic cell should be activated and depolarized before the levels of endocannabinoids concentration are increased in the postsynaptic cell. This will result in the diffusion of endocannabinoids as retrograde messengers back into the synaptic cleft. This will activate CB1R in the presynaptic axon, resulting in the blockade of Ca2+ conductance, preventing the further release of neurotransmitters (GABA) into the synaptic cleft. The prevention of GABA release will result in the excitation or disinhibition of the postsynaptic cell. - This process is called DSI because the inhibition of the GABA neuron on the postsynaptic cell is suppressed. This only occurs when the postsynaptic cell is depolarized by neighboring cells. Slide 9 - Under -80 mV, postsynaptic cells exhibit an inward conductance of Cl-. These currents are Cl- ions going into the cell as a result of the tonic activity of GABAergic interneurons. At rest, the GABAergic interneuron continuously releases GABA into the synaptic cleft, spontaneously activating GABA receptors, resulting in the inward conductance of Cl- into the cell. - When you stimulate the postsynaptic neuron by the patch electrode and then withdraw the stimulation, the spontaneous inhibitory postsynaptic Cl- currents would not immediately revert back to its baseline levels. There is about 5 seconds that the inhibitory postsynaptic current is suppressed. There are lower levels of inward current immediately after withdrawing the depolarization. - This demonstrates DSI. Once the neuron is depolarized, there will be an increased synthesis of endocannabinoids released in a retrograde manner into the synaptic cleft, activating endocannabinoid receptors expressed on the presynaptic axon, resulting in the inhibition of the release of GABA onto GABAergic receptors on the postsynaptic neuron, hence resulting in the suppression of inhibitory postsynaptic currents recorded in the postsynaptic cell. Slide 10 - DSI and DSE might be one of the mechanisms by which exogenous cannabinoids act. Slide 11
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