04. Biochemical aspects of neurons ====================================================================== LTP(long term potentiation): Generally, passed stimulus into brain are soon disappear. But LTP indicates to phenomemon where when stimulus worth to be remembered comes into brain, electric pulse of that stimulus sustains for long time (like over 10 hours). This phenomemon which has been intensively researched for last 30 years of neuroscience had been almost proved that it has something to do with phenomemon called memory. ====================================================================== When stimulus comes in, proteins are generated. Then, phase of spine separating almost shows up. After almost 1 hour, that spine actually becomes separated into 2 ones. ====================================================================== After forming action potential, there are much calcium channle around spine. There are 10000 times of calcium ion $$$Ca^{2+}$$$ around outside of cell than inside of cell. There are 10 times of sodium ion $$$Na^{+}$$$ around outside of cell than inside of cell. There are 20 times of potassium ion $$$K^{+}$$$ around inside of cell than outside of cell. Calcium had been chosen as "trigger" which triggers many and various reactions around overall cell. When action potential reaches to presynaptic membrane까지, calcium ion locating around outside of cell rushes into spine via calcium ion channel Then, vesicle locating in presynaptic membrane moves to end of membrane. Then, neurotrasmitters are released from vesicle towards synapse. If neurotrasmitters are attached onto receptors of postsynaptic membrane, molecules like glutamate, GABA, calcium ion are rushing into inside of postsynaptic membrane. Then, action potential is formed in the end. ====================================================================== Gap distance of synapse is 20nm, in other words, 200 angstrom. Radius of atom of hydrogen is 0.5 angstrom. Therefore, 200 angstrom of synapse gap can hold 400 number of atom of hydrogen. ====================================================================== You can observe end of spine by using TEM (Transmission Electon Microscope), which you can see something in x500K, x2000K zoom in. If you see board of silicon in x500K zoom in, you can see arrange of atom. You can see many holes at around end of spine. They're ion channel. ====================================================================== Importantly note that neurotrasmitter is what's attached onto receptors locating in surface of synapse. Then, those holes open. Then, molecules like $$$cl^{-}, Ca^{2+}$$$, glutamate, GABA, which are located in around synapse gap space enter into those opened holes. When especially glutamate is attached onto NMDA receptor, $$$Ca^{2+}$$$ goes into postsynaptic membrane. Therefore, memory reaction can be possible along with mutual reactions of proteins. ====================================================================== You can see "dark belt" around postsynaptic membrane. This dark belt is known as PSD-95 (postsynaptic density protein 95) where proteins are laid as like mat. On that mat, there are receptors. ====================================================================== Specific and physical evidence about enhacing memory is insertion of AMPA receptors onto postsynaptic membrane Insertion of AMPA receptors onto postsynaptic membrane is not simple reaction but it's formed by mutual reaction of many proteins. ====================================================================== Number of neurons of cerebral cortex is guessed as almost 14 billion. Each neuron can have almost 10000 spines. Therefore, when you think each neuron meets other neurons by using each set of 10000 spines, you can guess that there tons of connection in cerebral cortex (not entire brain though) ====================================================================== Most abundant neurotrasmitter (which takes 80 percent of portion) in cerebral cortex is glutamate which is promotive neurotrasmitter. Inhibitory neurotrasmitter is GABA which takes 20 percent of portion. Since inhibitory neurotrasmitter GABA makes electric pulse lower and lower towards negative voltage, GABA makes action potential hardly happen. ====================================================================== NMDAR, AMPAR are ionic receptor. mGluR is metabolic receptor. Metabolic receptor mGluR is enzyme and protein which is chained by thousands and 10 thousands of amino acids. mGluR pierces through membrane 7 times like sewing. ====================================================================== Based on mutual reactions from proteins, number of receptors increases or decreases. ====================================================================== Glutamate is attached onto NMDA receptor, then channel on spines opens, $$$Ca^{2+}$$$ rushes into inside of synapse via above opened holes, promoting mutual reactions of proteins. Finally, number of AMPAR receptor increases and memory becomes enhanced. ====================================================================== GABA and glutamate are immediately relased. So, they're called neurotrasmitter. However, we call dopamine, serotonin, noradrenalin, acetylcholine as neuromodulator. You can say neuromodulator makes atmosphere where neurotrasmitters can work more efficiently. ====================================================================== p1 There's presynaptic membrane (upper one which has vesicle) They're molecules which are containined in vesicle. In opposite direction, there is postsynaptic membrane. Ion channels (6 black dots) are inserted into postsynaptic membrane. ====================================================================== If you grasp 5-6 chemicals, you can apply them. Molecules which are contained in vesicle are: - dopamine(D) - serotonin(5'-HT) - acetylcholine (Ach: kind of Ach receptor is 2: muscarinic receptor and nicotine receptor) - noradrenalin(norepinephrine, NE) - adrenalin(epinephrine, E) - GABA ====================================================================== Next to synapse on both left and right side, you can see glial cell. Released chemicals can be collected by presynaptic membrane again, (note that arrow from synapse to presynaptic membrane) then collected ones can be used again. When being collected, in case of dopamine, dopamine is oxidized by monoamine oxidase (MAO) relased from mitochondrial outer membrane So that oxidized dopamine can't be used anymore. ====================================================================== There are some chemicals which are released from synapse and which work in similar way like MAO. One of them is catechol-O-methyl trasferase (COMT) By COMT, noradrenalin, dopamine, serotonin are converted into other chemicals around synapse. ====================================================================== Dopamine is originated from tyrosine. Tyrosine is one of 20 essential amino acid. If you draw molecular structure of tyrosine, you can see "amin" group based on C, C, and 2 Ns. H is attached onto C, remaining one location is attached by carboxyl group COOH. And hydroxy group HO is attached onto benzene ring. ====================================================================== L-DOPA is induced from tyrosine. Structure of right part is same but one more hydroxy group HO is attached. If you use decarboxylase, you can remove carboxyl group H from L-DOPA And result is dopamine. If $$$\beta$$$-Hydroxyase enzyme works on dopamine, it becomes noradrenalin. ====================================================================== Thre more OH shows up, the more reactions biochemically become active It's because when OH is inserted into existing structure, H becomes being out of it, becoming proton, resulting in more biochemical reactions. ====================================================================== noradrenalin is important chemical for attention. When proton H is ripped off from amine group of noradrenalin, and when methyl group $$$CH_{3}$$$ is attached, it's adrenalin ====================================================================== Note that there are Cs in ring of benzene And connected Hs to Cs are omitted for simplicity. Atomic value of C is 4. When you rip off H from C, H becomes proton. You can attache OH onto ripped location. Protein and enzyme intervene these reactions for ripping off and attatching something. ====================================================================== Relationship between enzyme and protein is same with relationship between key and locker. If you use locker with key, hole of locker for key becomes loosen, resulting in error in 3D structure. Therefore, you should create protein (like locker) every time. Proteins in brarin are newly generated and replace with old ones within almost 2 weeks. Ion channels like AMPAR channel automatically decomposes within 20 minutes if there's no relavent stimulus. And then decomposed ion channel is newly created. Growth rate of neural branch is 40$$$\mu$$$m/h 40$$$\mu$$$m/h means neural branch grows 40 micro meter per hour. Size of neuron is 20-50 micro meter. If size of one neuron is 20 micro meter, neural branch can grow 2 times in size within 1 hour. Phospholipid bilayer of ion channel Speed of ion channel in phospholipid bilayer is 3$$$\mu$$$m/min In case of AMPAR channel, size of ion channel is 10 $$$\mu$$$m. Speed of blood stream and red cell in capillary vessel is 1mm/sec If you know these numerics, you can perceive dynamics of the life. ====================================================================== Chemicals like dopamine, serotonin, noradrenalin are toxic chemicals in some way. That's why those chemicals should stay inside of synapse gap, shouldn't be leaked into other areas. Besides, after using those chemicals, you should collect them to reuse, should perform oxidation treatment on them as insolvency treatment. Chemicals which are in charge of these processes are COMT, MAO, etc. ====================================================================== C out of COMT is catechol. Catechol is dihydroxl benzene where 2 of hydroxy group OH are attached onto benzene ring. Therefore, we would also say neurotrasmitter as catechol amine ====================================================================== There are purkinje cells in cerebellar cortex. On one purkinje cells, there can be almost 10000 spines.