Synapse / Action potential

027bNodes of Ranvier

the junction between two adjacent myelin segment.

011Neurotransmitters and area of concentration

ACh is excitatory neruotransmitter for NMJ, LEMS, Myasthenic Gravis Autonomic nervous system Norepinepherin : Excitatory & Inhibitory. Serotonin : Excitatory & Inhibitory. Excitatory transmitter for the CNS Glutamate: wide distribution, excitotoxic cell death, Seizures Inhibitory transmitter Dopamine: Parkinson's Disease: GABA : Epilepsy Glycine: only spinal cord

021Action potential is generated at

Action potential is generated at the axon initial segment. Each synaptic inputs at the dendrites and cell body cause slight depolarization of this post-synaptic neuron. These slight depolarization accumulate and eventually exceed the threshold. The voltage gated Na-channel concentrated at the "axon initial segment" will open and generate an action potential. Thus, the action potential is first generated at the axon initial segment. Axon hillock is the stem of the axon, near the cell body The AP is generated only when the depolarization exceeds the threshold, in an "all or none" fashion. Once the AP is generated, it will propagate down the axon, information is passed on to the next neuron.

004Synaptic Vesicle Fusion

Ca++-induced vesicle fusion Required proteins: SNARE proteins: synaptobrevin, snap-25, and syntaxin Calcium sensor: synaptotagamin The membrane added by this fusion is later retrieved by endocytosis and recycled for the formation of fresh neurotransmitter-filled vesicles.

2Electrical and Chemical Synapses

Chemical Synapse (Majority) •Vesicle cluster •Clear space between membranes (20-40nm) Electrical Synapse (Gap Junction) •Very close apposition of membranes (~3nm) •Dense material in contact area

031Myelin Structure

Difference of PNS vs CNS : extracellular space. CNS: Proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG), oligodendrocyte myelin glycoprotein (OMgp) PNS: Protein 0 (P0), peripheral myelin protein of 22 kDa (PMP22), myelin basic protein (MBP)

Excitatory and inhibitory neurotransmitters

EXCITATORY ACh: LEMS, Myasthenic Gravis. INHIBITORY Glutamate: Excitotoxic cell death, Seizures. Dopamine: Parkinson's Disease. GABA: Epilepsy.

Inhibitory actions at chemical synapses

Excitatory synapse: excitatory postsynaptic potential (EPSP) - depolarization - action potential Inhibitory synapse: inhibitory postsynaptic potential (IPSP) - hyperpolarization - Ligand gated Cl- channels -An EPSP makes it more likely for a postsynaptic neuron to generate an action potential, whereas an IPSP makes it more difficult for a postsynaptic neuron to generate an action potential. -Whether a synapse is excitatory or inhibitory depends on what type(s) of ion channel conduct the post-synaptic current display(s), which in turn is a function of the type of receptors and neurotransmitter employed at the synapse.

026Myelin

Glia cells, Schwann cells and Oligodendrocytes. Myelin surround axons. Myelin sheath is generated by specific type of glia. Central nervous system ; Oligodendrocyte. Single Oligodendrocyte make multiple myelin segment. Peripheral nervous system: Schwann cell. Single Schwann cell will make one myelin segment.

025Excitatory and Inhibitory neuron

Knee jerk reflex circuit: MN innervating quadriceps needs to excite, and induce contraction. MN innervating hamstring needs to relax, and not induce muscle contraction. This is the role of an inhibitory neuron, not the excite the innervating neuron.

007Size difference of synapses

Neuromuscular junction = Synapse of motor neuron and muscle Amyotrophic lateral sclerosis (ALS) Hippocampus very important to learning.

005Cleavage of SNARE proteins by clostridial toxins

Neurotoxins from botulinum and tetanus Tetanus toxin specifically cleaves synaptobrevin (VAMP) (Typically taken up by spinal cord interneurons) Botulinum toxins (types B, D, F, and G) specifically cleave the vesicle SNARE protein, synaptobrevin Botulinum toxin (type C) cleave syntaxin Botulinum toxins (types A and E) cleave SNAP-25

013The general architecture of ligand-gated receptors

Neurotransmitter receptors AMPA receptors: GluR 1-4 Ligand-gated receptors Excitatory Metabotropic Glutamate receptor: mGluR 1-8 G-protein coupled receptors Metabotropic receptors class I = Excitatory Metabotropic receptors class II, III = inhibitory

029Peripheral Nerve

Peripheral nerve Axon, Schwann cells Endoneurium: associated with individual nerve fibers. Loose connective tissue layer, collagen fibrils. Perineurium: blood-nerve barrier, diffusion barrier similar to BBB, connective tissue cells. Epineurium: dense irregular connective tissue, surrounds the entire nerve and blood vessels.

027Schwann cell

Peripheral nervous system: Schwann cells. Single Schwann cell myelinate one axon.

010Synapse of enteric nervous system

Synapse of autonomic nervous system are different Presynaptic terminals: varicosities, enlarged region of nerves Post synaptic site: Not clearly defined. Distance from the presynaptic varicosity.

008Myasthenia gravis

autoantibodies against the postsynaptic acetylcholine receptor. Reduced AChR, reduced neurotransmission, weakening of muscle

009Lambert-Eaton Syndrome

reduction in transmitter release autoantibodies to own Ca+2 channels, block voltage-gated Ca+2 channels. reduced neurotransmission, weakening of muscle Often associated with lung cancer.

006Electrical synapses by Gap Junctions

• 6 Connexins form 1 connexon • 2 connexons form 1 gap junctional channel • Fast transmission • Synchronization of inhibition • Low-pass filter • Gap junctional coupling is regulated

Chemical Synapses

• Connection between neuron and target cell where information is exchanged. • Presynaptic terminal onto postsynaptic target cell. • Synaptic vesicles (SV) • Dendritic Spines

Sequence of events involved in transmission at a typical chemical synapse

- Vesicles containing neurotransmitter sit "docked" and ready at the synaptic membrane. - The action potential produces an influx of calcium ions through voltage-dependent, calcium-selective ion channels. - Calcium ions trigger vesicles to fuse with the presynaptic-membrane and releasing their contents into the synaptic cleft. Sequence of events at the chemical synaptic. 1) Neurotransmitter is synthesized and then stored in synaptic vesicles. 2) Action potential invades the presynaptic terminal. 3) Depolarization of presynaptic terminal causes opening of voltage-gated Ca channels. 4) Influx of Ca ions through channels. 5) Ca ions causes synaptic vesicles to fuse with presynaptic membrane. 6) Neurotransmitter is released into synaptic cleft via exocytosis. 7)Transmitter binds to receptor molecules in postsynaptic membrane. 8) Opening or closing of postsynaptic channels. 9) Postsynaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the postsynaptic cell. 10) Retrieval of vesicular membrane from plasma membrane, by endocytosis involving Clathrin.

Multiple Sclerosis (MS)

-Chronic disease of the CNS, predominantly affects young adults. -Autoimmune and/or viral disease, but genetic and environmental factors may contribute (women > men, north > south). -Characterized by areas of demyelination and T-cell predominant perivascular inflammation in the brain white matter. -Symptoms include numbness, paresthesia, double vision, optic neuritis, ataxia, and bladder control problems. Subsequent symptoms involve upper motor neurons: spasticity, para- or quardriparesis. Vertigo, incoordination and other cerebellar problems, depression, emotional lability, gait abnormalities, dysarthria, fatigue and pain.

012Excitatory and Inhibitory neuron

...

014Neurotransmitter and drug similarity

...

016Propagation of action potential

...

024Generation of Action Potential at 3 different points

...

023The action potential propagates in one direction, because

1) AP is generated at the axon hillock and start propagating. 2) After AP, voltage gated potassium channel will open and keep the axon hyperpolarized.

018Ion selective channels and Equilibrium potential

1) In a cell permeable only to K ion, the membrane potential is generated by the efflux of K down its concentration gradient. 2) The continued efflux of K ion builds up an excess positive charge on the outside of the cell and leaves behind on the inside an excess negative charge. 3) This build-up of charge leads to a potential difference across the membrane. 4) This potential impedes the further efflux of K ion and equilibrium is reached. Chemical driving force : movement of ions by concentration difference. Electrical driving force: movement of ions by electrical potential. At this point, the two driving force are equal and opposite. As many K ion move out as move in. This electrical potential generated across the membrane is called "equilibrium potential". -75mV for K ion of squid axon. Same logic applies to Na ion, and the equilibrium potential is +55mV.

015Synaptic transmission and psychoactive drug

1a) Increase of synthesis (L-DOPA) 1b) Inhibition of synthesis (antipsychotic: alpha-methyltyrosine) 2) Interferene with vesicular storage (antipsychotic: reserpine, tetrabenazine) 3) Stimulation of release of DA at the nerve terminal (amphetamine, tyramide) 4) Blocking of DA receptors and autoreceptors (antipsychotics: perphenazine, haloperidol) 5) Inhibition of reuptake (cocaine, amphetamine, benztropine) 6) Inhibition of breakdown (pargyline) 1a, 3, 5, 6: can produce psychotic symptoms Too much dopamine leads to schizophrenia and Too little leads to Parkinsons.

030oligodendrocyte

An oligodendrocyte wraps multiple axons. Central nervous system ; Oligodendrocyte. Single Oligodendrocyte myelinate several axons. Node of Ranvier is larger than those of PNS, which makes the saltatory conduction more efficient.

1Synapses

Axosomatic: Presynapse = Axon, Postsynaptic site = cell body. Axodendritic: Presynapse = Axon, Postsynaptic site = dendrite. Axo-axonic: Presynapse = Axon, Postsynaptic site = axon terminal.

033Myelin and Saltatory Conductance

Myelin and Saltatory conductance will allow fast transmission of action potential. If an axon is demyelinated, action potential may not regenerate. Because enough current may not reach the area rich in voltage gated Na channels, former area of node of Ranvier. The current will only spread passively, and eventually decay, and action potential will be lost.

032Saltatory conduction of action potential

Myelin sheath has many layer of membrane, and it will function as an insulator. Plus, voltage gated sodium channels are sparse under the Myelin segment. Thus Myelinated area will not pass currents. Voltage gated Na and K channels are concentrated at the nodes of Ranvier. Thus, the depolarizing current will travel down the axon and regenerate at the nodes. This type of AP propagation is called "saltatory conductance", like jumping. Action potential will propagate from a node to the next node. Thus, Myelin sheath allows fast and longer transmission of action potential.

019Resting membrane potential

The nerve membrane has potassium ion selective channels that are open at resting state (when there is no action potential). There are many potassium selective channels, and they will generate resting membrane potential at -75mV. There are also few sodium selective channel open. Sodium ions will rush into the cell, because the cytosolic concentration of Na is low. Both the chemical and electrical driving forces are pushing Na ions to go in. There are more K channels than sodium channels. So the contribution of Na conductance is small, only to bring the membrane potential to -60mV. As a sum, the ion distribution and channels make the neurons negative inside compared to the extracellular space.

017Sodium-Potassium pump

The neurons have Sodium-Potassium pump on the plasma membrane. The pump hydrolyzes one molecule of ATP to exclude 3 Na+ ions and bring in 2 K+ ions. This active process generates concentration differences across the membrane.

020Sequential opening of Voltage-gated Na, K channels generate action potential

These are voltage gated channels, and different from the channels forming the resting membrane potential. During the action potential (reddish-brown), voltage gated sodium channel and voltage gated potassium channel open sequentially. These voltage gated channels have several intrinsic properties Sense depolarization and open Na-channel open fast and close quickly (purple). K-channel open slowly and close slowly (purple). The mechanism step by step. The resting membrane potential is close to the equilibrium potential of potassium. depolarization of membrane potential will reach the threshold. The voltage gated Na-Channels will sense the depolarization and open first. Cytosolic [Na] is low, so the Na ions will rush in, driving the membrane potential towards the equilibrium potential of Na ion, +55mV. 5) Steep rise of the membrane potential = action potential. 6) The voltage gated K-channels also sense the depolarization and open next slowly. 7) Na channel will get inactivated and close. 8) Cytosolic [K] is high, so the K ions flow out, making inside negative, driving the membrane potential towards the equilibrium potential of K ion, -75 mV 9) Long open K channel will drive the membrane potential lower, "after potential". 10) K channel close and the membrane potential back to the resting membrane potential. (Refractory Period)

022Action potential propagation

Two important aspect for the propagation of an action potential. 1) Cable properties: current will passively flow where the resistance is least. The current will flow down the axon passively. The current will decrease as it travels further, because they escape through the channels on the membrane. 2) Voltage gated Na-channel will open by depolarization current generated by the action potential. The opening of VGCC will generate a new action potential, regeneration of an AP.

Summary

Two types of synapses, electrical, chemical. Electrical synapses (gap junctions) are comprised of connexins. The sequence of events at a chemical synapse (calcium influx, synaptic vesicle, neurotransmitter release, binding to postsynaptic membrane receptors). Types of neurotransmitters (excitatory, inhibitory). Postsynaptic receptors (ion channels versus G protein-coupled receptors). Mechanisms that generate resting membrane potential in a neuron. Ion selective channels, Na/K pump Mechanisms to generate an action potential in a neuron. Voltage gated channels Axon hillock, axon initial segment Excitatory, inhibitory synapse EPSP, IPSP, Cl-channel Mechanisms that allow saltatory conduction. Oligodendrocyte, Schwann cells Myelin sheath, node of Ranvier Multiple sclerosis, demyelination

034Wallerian degeneration

Wallerian degeneration: rapid axon degeneration mechanism after axotomy, related to axon dying back neurodegenerative diseases.