Ch.6 Synaptic Transmission

Cholinergic Receptors

(Nicotinic and Muscarinic) 1. Nicotinic- Two Subtypes that increase cation (Na+, K+) permeability: Muscle Type (Nm): Skeletal muscle Neuronal Type (Nn): Peripheral and Central Nervous Systems Nicotine is an Agonist of both Nm and Nn receptors. Succinylcholine is an agonist at Nm receptors while d-Tubocurarine is an antagonist. 2. Muscarinic- All Muscarinic Receptors are GPCRs 5 sub-types (M1, M2, M3, M4, M5). Mostly found on effector organs of the parasympathetic nervous system. M1, M3, and M5 receptors activate Gq-PLC receptors causing an increase in intracellular Ca2+ and causing a variety of Ca2+-mediated responses. M2 and M4 receptors inhibit adenylyl cyclase and regulate specific ion channels via coupling Gi/o. Responses to muscarinic agonists are slower. Responses may be either excitatory or inhibitory and are not necessarily linked to changes in ion permeability.

Chemical Synapses

(most of what we will cover) 1. A pre-synaptic neuron and a post-synaptic neuron separated by a synaptic cleft (30-50 nm wide). 2. Communication by neurotransmitters. 3. 3 Types of chemical synapses: -Axodendritic -Axosomatic -Axoaxonic 4. Gap is the synaptic cleft (narrow). Axodendrtitic- axon and dendrite. Axosomatic- axon talking to cell body. Axoaxonic- regulate how much of the NT will be realeased on other neuron. Chemical is only for one way flow 5. Chemical synapses allow for unidirectional communication only. The pre-synaptic neuron communicates with the post-synaptic neuron. The terms pre- and post- are relative to a specific synapse.

Pre-Synaptic Inhibition

1. A's effect is to DECREASE the amount of NT released by excitatory neuron B. How does it do this? 2. Inhibition occurs due to increased Cl- conductance (reduces AP size) which decreases the Ca2+ entry into neuron B's synaptic terminal and the amount of excitatory NT it releases. 3. Remember A is not synapsing with C

Pre-Synaptic Facilitation

1. A's effect is to INCREASE the amount of NT released by excitatory neuron B. How does it do this? 2.Facilitation occurs due to increased AP time so there is increased Ca2+ entry and more NT is released by neuron B. 3. Presynaptic Inputs Change Action Potentials 4. Neuron A increases how much NT B releases onto C. This AP is lasting longer. More Ca will enter. Thus a bigger EPSP in neuron C, and a bigger GP

Dopamine

1. CNS neurotransmitter 2. Either excitatory or inhibitory depending on which receptor is activated. 5 receptor subtypes - D1, D2, D3, D4, D5 (all metabotropic) Functions in behavior, cognition, voluntary movement, sleep, mood and learning and the reward system. Insufficient dopamine biosynthesis in the dopaminergic neurons can cause Parkinson's Disease

Serotonin: 5-Hydroxytryptomine (5-HT)

1. CNS neurotransmitter 2. Functions Include: Sleep Cognition Sensory perception, Motor activity Temperature regulation Nociception Mood Appetite Sexual behavior Hormone secretion 3. The 5-HT receptor subtypes are the largest (14) known NT-receptor family. 4. Serotonin (degradation or re-uptake) is a target in the treatment for depression. SSRI: Selective Serotonin Re-uptake Inhibitors MAOI: Monoamine Oxidase Inhibitor Serotonin is involved in a lot of things. SSRI blocking uptake increase serotonin levels

LTP at Glutamate Synapses

1. Cooperative activity of AMPA and NMDA receptors has been implicated in a phenomenon called long-term potentiation (LTP). 2. This mechanism couples frequent activity across a synapse with lasting changes in the strength of signaling across that synapse, and is thus thought to be a cellular process underlying learning and memory. When two neurons communicate a lot, they get better at that communication. Enhances a synapse in its ability to communicate. Such as learning, uses LTP.

EPSP: increases AP Likelihood

1. Depolarization produced by either opening or closing channels. 2. Moves membrane potential towards the threshold potential. 3. How could closing a channel lead to an EPSP? 4. Net Na+ influx causes depolarization 5. K+ channel CLOSES, K+ cannot move through channel causing depolarization 6. Get a depolarizing event. Just graded potentials. Na will have more membrane movement here. Also closing K channel depolarizes membrane. The G protein here is a Gs because producing more cAMP. Gs means cAMP goes up (not necessarily that channel is opening or closing) and the protein being phosphorylated is actually the Ion channel. This case the K is closing

Acetylcholine

1. Found in PNS and CNS 2. Most abundant NT in PNS 3. Synthesis and Breakdown 4. It is a cholinergic neuron means its making acetylcholine. AcetylCoA + Choline = Acetylcholine. Package it in vesicles. When Ca channels open we have exocytosis and release Acetylcholine. Acetylcholinesterase breaks down acetylcholine, putting it back into its constintuents. Thus, neuron can recycle it. Acetycholine can beind to autoreceptors (negative feedback), heteroreceptors wil also bind to other NT that will inhibit acetylcholine release (presynaptic inhibition) axo-axonic synpase

Glutamate

1. Glutamate is estimated to be the primary neurotransmitter at 50 percent of the excitatory synapses in the CNS! There are 2 types of receptors: 1. Metabotropic (mGluR) 2. Ionotropic a. AMPA: identified by their binding to a-amino-3 hydroxy-5 methyl-4 isoxazole proprionic acid) b. NMDA: bind N-methyl-D-aspartate

Classes of Chemicals Know or Presumed to be Neurotransmitters or Neuromodulators

1. Neurons are often described based on the neurotransmitter they release (using the suffix -ergic). For example: -Acetylcholine releasing neuron: Cholinergic -Dopamine releasing neuron: Dopaminergic -Neurons that release EPI and NE are called Adrenergic. 2. The receptors to which these NTs bind are also named using these terms (Cholinergic Receptors bind ACH, Adrenergic Receptors bind EPI and NE). A category of Biogenic amines is catecholamines (which includes dopamine, NE, and Epi). also serotonin and histamine are biogenic amines.

IPSP: Decreases AP likelihood

1. Neurotransmitter binds to receptor 2. Channels for either K+ or Cl- open 3. If K channels open: - K+ moves out --> IPSP 4. If Cl- channels open: - Cl- moves in --> IPSP or -Cl- stabilizes Cl will do different thngs in different cells.1) can stabilized membrane potential or 2) produce an IPSP (moving away from threshold) some cells have Cl pumps (actively pumping Cl out, thus Cl is not at equilibrium) Moves membrane potential away from the threshold potential.

Norepinephrine and Epinephrine

1. Norepinephrine (NE) is in the CNS and PNS. In the PNS, NE is released onto target organs of the Sympathetic NS. 2. Epinephrine (EPI) comes from CNS, but is more commonly released as a neurohormone by the adrenal medulla. 3. Adrenergic receptors- α1, α2, β1, β2, β3 4. All adrenergic receptors are GPCR -β1, β2, β3 Gs coupled - α1 is Gq coupled -α2 is Gi coupled

Pre-Synaptic Synapses

1. The regulation of communication at Axoaxonic Synapses. 2. Function as modulatory synapses -Regulate the amount of calcium that enters the synaptic terminal in response to an AP, which alters the amount of NT released. 3. Can either facilitate or inhibit transmission (Presynaptic Facilitation Presynaptic Inhibition) 4. ( in reference to PP 17) Neuron A is exerting a pre-synaptic effect on the synapse between B and C. Presynaptic Inputs Change Action PotentialNeuron A is exerting a pre-synaptic effect on the synapse between B and C. Neuron A talks to neuron B, not neuron C directly. A will dictate the degree of NT release by B when B is active. A can either facilitate or inhibit B's NT rate. These can change action potentials produced in the synaptic terminal.

Modulation of NE Release

1. There are adrenergic receptors on the pre-synaptic nerve terminal which bind to NE and they can cause more (B2) or less NE release (α2). These are called autoreceptors. 2. Heteroreceptors on the pre-synaptic nerve terminal also modulate NE release. Receptors for acetylcholine, histamine, serotonin, and prostaglandins have been identified. PP slide 28 These are axoaxonic receptors.

Electrical synapses

1. Two neurons linked together by gap junctions 2. Some are between neurons and glial cells 3. Functions in the nervous system: -Rapid communication -Ions or second messengers -Usually bidirectional communication -Excitation and inhibition at the same synapse -Identified in the retina, cortex, brainstem (breathing), and hypothalamus (neuroendocrine neurons 4. Physically connected using proteins. Nervous system uses gap junction. Faster mode of communication.

example of SNARE protein

1. Vesicle fusion with the membrane involves SNARE proteins 2. Botulinum neurotoxin cleaves the SNARE protein complex, which prevents exocytosis of ACH into the cleft. Low doses of botulinum toxin (Botox) can be used to treat excessive sweating, migraines, muscular disorders. Botulism, an illness caused by toxin produced by Clostridium botulinum, can cause respiratory failure and death. 3. Atp is used for docking and priming. Calcium is main component for exocytosis. Calcium enables SNARE interaction (don't need to know details)

Receptors at Chemical Synapses

1.Ionotropic Receptors -Nicotinic ACH receptor: Na+, K+ channel -Glycine Receptor: Cl- channel -GABAA Receptor: Cl- channel -NMDA: Non-specific cation channel -AMPA: Non-specific cation channel 2. Metabotropic receptors (GPCR) -Muscarinic ACH receptor -α1, α2, β1, β2, β3 adrenergic receptors for NE/EPI -Dopamine Receptors (D1-D5) -GABAB Receptor Opening of ion channels leads to a graded potential, which can either activate or inhibit the target cell. GPCRs can open/close ion channels, too.

How do drugs alter synaptic communication?

A drug might 1. increase leakage of NT from vesicle to cytoplasm, exposing it to enzyme breakdown 2. Increase transmitter release into cleft 3. block transmitter release 4. inhibit transmitter synthesis 5. block transmitter reuptake 6. block cleft or intracellular enzymes that metabolize transmitter 7. bind to receptor on postsynaptic membrane to block (antagonist) or mimic (agonist) transmitter action 8. inhibit or stimulate second-messenger activity within postsynaptic cell

Amino Acid Neurotransmitters

At excitatory synapses (produce EPSPs) 1. Aspartate (non-specific cation channel) 2.Glutamate (non-specific cation channel) -AMPA -NMDA At inhibitory synapses (produce IPSPs) 1. Glycine (Cl- Channel) 2. GABA (GABAA receptor: Cl- channel) Gluatamate and Apsartate are both excitatory. Glycine and GABA are inhibitory

Histamine

CNS neurotransmitter, but also involved in immune and digestive functions in the periphery.

Postsynaptic Potentials (PSP): Graded Potentials

Change in membrane potential in response to receptor-NT binding 1. Excitatory postsynaptic potential (EPSP) -Depolarizing Graded Potential -Increases the likelihood of an AP -Most common excitatory NT: glutamate 2. Inhibitory postsynaptic potential (IPSP) -Hyperpolarizing Graded Potential -Decreases the likelihood of an AP -Most common inhibitory NT: GABA EPSP gets you closer to threshold.

Cl channels con't

Cl has a different Ep due to pump actively pumping(using ATP) Cl- out. So, a NT could come in and bind causing Cl to come in(moving closer to Ep) and cause an IPSP. (thus Glycine and GABAa are inhibitory receptors) Some cells don't actively pump Cl out, thus allowing Cl to remain near equilibrium. Top right and bottom right are gated Cl Still called and inhibitory input since we are cancelling out an excitatory input. May need to look at PP slide 12

Synaptic Integration

Neuronal arrangements: 1. Divergence: ONE pre-synaptic neuron synapses with several post-synaptic neurons 2. Convergence: MANY pre-synaptic neurons synapse with one post-synaptic neuron. 3. Graded potentials can sum together: -Temporal: one presynaptic neuron fires repeatedly -Spatial: several presynaptic neurons fire at the same time Neurons make and secrete just one neurotransmitter (so if there are two NT coming to cell than there were 2 neurons) Divergence is found in the sympathetic division.

Synaptic cleft/ space

Synaptic delay of at least 0.5 ms between the pre-synaptic depolarization and post-synaptic response. -Due to time for calcium entry for exocytosis, presynaptic neurotransmitter release, diffusion in the synaptic cleft, and postsynaptic receptor activation. -Allows one to gauge the complexity of a reflex pathway (number of synapses) by looking at the speed of the reflex.

Synaptic Integration con't

TEMPORAL Summation: More APs in one pre-synaptic neuron result in more neurotransmitter release and, consequently, a greater IPSP or EPSP in the next neuron SPATIAL Summation: Simultaneous APs in several pre-synaptic neurons result in more neurotransmitter release and, consequently, the EPSP and/or IPSP's sum together. This can be additive or subtractive in nature. (reference to PP 16) You can have both. AA and BB are temporal, spatial would be combination of both firing. C is an inhibitory axosomatic synapase. A and B are axodendritic synapses

What dictates the strength of a synapse?

There are presynaptic factors (like availability of NT, axon terminal membrane potential, activation of membrane receptors on presynaptic terminal etc.) There are also postsynaptic factors and general factors Axo-axonic synapses effect how much NT gets released. Autoreceptors are on the presynaptic neuron.

MAO and COMT

Enzymes for degrading biogenic amines: 1. Monoamine oxidase (MAO) 2. Catechol-O-methyltransferase (COMT) Need to know MAO and COMT. MAO inhibitors allows for more dopamine to be released and bind to more receptors.

Sequence of Events at a Chemical Synapse

Here is the sequence: 1. AP reaches terminal 2. Voltage-gated Ca2+ channes open 3. Calcium enters axon terminal 4. NT is released and diffuses into the cleft 5. NT binds to postsynaptic receptors 6. NT removed from synaptic cleft It is the receptor, not the NT, that determines the response generated in the post-synaptic cell. A lot of voltage gated in synaptic terminals, thus calcium is being driven in through the concentration gradient. (stronger than electrical gradient) results in neurotransmitter release which bind to receptors

Biogenic amines

Includes: Catecholamines: Dopamine, Norepinephrine (NE), Epinephrine (EPI) Histamine Serotonin (5-HT)