History & Function of Brain Synapses

• The brain was believed to be vital to life in prehistoric times, as evidenced by skull surgeries (trepanation).
• Ancient Egyptians thought the heart was the source of the soul and memory.
• Ancient Greeks correlated brain structure and function, with Hippocrates discovering the brain's role in sensation and intelligence.
• Galen, in Roman times, believed the cerebrum was responsible for sensation and the cerebellum for muscular control, and identified ventricles.
• In the 17th century, the brain was viewed as a machine, with the fluid mechanical theory suggesting fluid from ventricles moved limbs by inflating muscles.
• Descartes introduced the philosophical mind/brain problem in the 17th century.
• The 17th and 18th centuries saw the identification of gray and white matter, detailed gross anatomy, and identification of gyri, sulci, and fissures in the brain.
• Subdivisions of the brain and spinal cord were identified, along with the peripheral division of nerves.
• During the 19th century, nerves were understood as wires, leading to an electrical understanding of the nervous system.
• Bell & Magendie identified dorsal and ventral roots carrying information in opposite directions.
• Charles Bell, Franz Joseph Gall, Marie Jean Pierre Flourens, and Paul Broca were key figures in identifying localization of function in the brain.
• Charles Bell determined the cerebellum to be the origin of motor fibers and the cerebrum the origin of sensory fibers.
• Franz Joseph Gall founded phrenology, linking bumps on the skull surface to brain surface and personality traits.
• Marie Jean Pierre Flourens used detailed experimental ablation methods.
• Paul Broca identified a discrete region of the human cerebrum responsible for speech.
• Darwin's theory included the evolution of the nervous system and natural selection, with nervous systems of different species sharing common mechanisms.
• Darwin's theories gave rationale for animal models in neuroscience.
• Cell theory states the neuron is the basic functional unit of the brain.
• The scientific process involves observation, replication, interpretation, and verification.
• Animal use in neuro research is guided by evolutionary relationships and moral responsibilities, with simpler processes studied in more distant relatives of humans.
• Glia insulate, support, and nourish neurons.
• Neurons process information, sense environmental changes, communicate these changes, and command bodily responses.
• Histology is the microscopic study of tissue structure.
• Nissl stain facilitates the study/visualization of the central nervous system by staining negatively charged cellular components.
• Golgi stain, a silver stain, reveals the cell body and neurites.
• Camillo Golgi believed neurons were fused together, while Santiago Cajal believed they were individual and communicated through contact.
• The human eye can distinguish objects more than 100µm apart, while neurons have a diameter of 20µm, and light microscopes have a limited resolution of 0.1µm.
• Neurons are about 20 nm apart.
• The soma is made up of cytosol, organelles, and cytoplasm.
• The neuron's nucleus is responsible for gene expression, transcription, and RNA processing.
• Knockout mice have a deleted gene, transgenic mice have introduced and overexpressed foreign genes, and knock-in mice have a native gene replaced with a modified version.
• The ribosome is the site of protein synthesis.
• Smooth ER and Golgi are the sites of protein packaging, sorting, and trafficking.
• Mitochondria is the site of cellular respiration and makes ATP.
• The cytoskeleton, made of microtubules, neurofilaments, & microfilaments, is the internal scaffolding of the neuronal membrane and is not static.
• The neuronal membrane is approximately 5nm thick, and its structure influences neuronal function.
• The axon hillock is the beginning of the axon that connects to the soma.
• The axon proper is the middle of the axon and is myelinated.
• The axon terminal is the end of the axon where the synapse occurs.
• The cytoplasm of the axon terminal contains unique proteins, mitochondria, synaptic vesicles, and membrane proteins.
• Synaptic transmission is electrical to chemical to electrical and synaptic transmission dysfunction leads to mental disorders.
• Axoplasmic transport can be anterograde (soma to terminal) or retrograde (terminal to soma).
• Dendrites are the antenna of the neuron, create trees and branches, and dendritic spines receive signals from axon terminals.
• Neurons can be classified by number of neurites, dendritic and synaptic morphology, connections with the CNS, axonal length, gene expression, and neurotransmitter type.
• A unipolar neuron has a single neurite coming from the soma, a bipolar neuron has two, and a multipolar neuron has multiple.
• Neurons can be stellate (star-shaped) or pyramidal (pyramid-shaped).
• Spiny neurons have dendritic spines, while aspinous neurons don't.
• Type 1 Golgi neurons have long axons to communicate with the nervous system, and type 2 Golgi have short axons acting as local circuits (interneurons).
• Astrocytes are the most present glial cell in the brain, filling spaces between neurons, influencing neurite growth, and regulating the chemical content of the extracellular space.
• Myelinating glia insulate axons and oligodendroglia (CNS) and schwann cells (PNS).
• Ependymal cells secrete spinal fluid, and microglia support immune functions.
• Neurophysiology is the study of electrical and chemical processes in neurons.
• Information flows within a neuron via electrical signals and passes between neurons through chemical signals.
• Cytosol and extracellular fluid contain water (main ingredient) and dissolved ions (responsible for charge in neuron).
• Cations are atoms with a net positive charge, and anions are atoms with a net negative charge.
• Hydrophilic compounds dissolve in water due to uneven electrical charge across a polar bond while hydrophobic compounds don't dissolve in water due to even electrical charge across a nonpolar bond.
• Proteins in the phospholipid bilayer control resting and action potentials, have polar and nonpolar R groups to interact with intra and extracellular fluid, and have ion selectivity and gating.
• Ion pumps, formed by membrane-spanning proteins, use energy from ATP and are important for neuronal signaling.
• Diffusion of ions: dissolved ions will distribute themselves evenly across a membrane.
• Ions flow down the concentration gradient when channels are permeable to specific ions and a concentration gradient exists across the membrane (unequal charges across membrane).
• Electrical current (I) influences ion movement.
• Factors that determine how much current will flow include electrical potential (voltage) and electrical conductance.
• Electrical potential/voltage is the force exerted on charged particle.
• Electrical conductance is the relative ability of electrical charge to migrate from one point to another.
• Driving an ion across a membrane requires that the membrane has channels permeable to the ion and an electrical potential difference across the membrane.
• Membrane potential (Vm) is the voltage across the neuronal membrane at any moment, changes during action potential, and is at rest around -65mV.
• Ohm's Law: I=gV.
• Equilibrium potential (Eion) is the electrical potential difference that exactly balances the ionic concentration gradient, with no net movement of ions when separated by cellular membrane.
• Equilibrium potential reached with K+ channels.
• Equilibrium potential involves large changes in Vm and net difference in electrical charge inside and outside cell.
• Ionic driving force can be calculated using the rate of movement of ions across the membrane (proportional Vm-Eion).
• Nernst equation calculates the exact value of equilibrium potential for each ion in mV.
• The Nernst equation considers the charge of the ion, temperature, and ratio of external and internal ion concentrations.
• Calcium pumps actively transport Ca2+ out of the cell.
• Membrane permeability determines membrane potential.
• The Goldman equation takes into account the permeability of the membrane to different ions.
• Potassium channels have 4 subunits, and selective permeability is a key determinant of resting membrane potential.
• Resting membrane potential is close to Ek because it is mostly permeable to K+.
• Membrane potential is sensitive to extracellular K+.
• Increased extracellular K+ depolarizes the membrane.
• Mechanisms regulating external potassium concentration include the blood-brain barrier and potassium spatial buffering by astrocytes.
• The sodium-potassium pump is an enzyme that breaks down ATP when Na+ is present, pumping 3 Na+ out for every 2 K+ ions coming in.
• The sodium-potassium pump sets up an electrical gradient in the cell.
• Action potential steps:
  • 1. Na+/K+ pump decreases membrane potential and sets up electrical gradient (-5mV).
  • 2. Leaky K+ channels let K+ out BUT leave anions behind in cell (-90mV).
  • 3. Leaky Na+ channels let more Na+ into cell (-70mV).
• Voltage is the difference in charge between 2 points (mV).
• Current is the rate at which charge is flowing (nanoamperes).
• The action potential is generated by depolarization of the membrane beyond threshold (~-55mV).
• Action potentials convey information over long distances and represent a reversal of charge relative to the extracellular space.
• Potassium and sodium gates both open in response to depolarization.
• Potassium gates open later than sodium gates, and potassium conductance resets membrane potentials.
• Sodium channels have 6 membrane-spanning units repeating 4 times.
• Sodium channels open with little delay and cannot be opened again immediately after.
• Chlorine channels are made of 2 proteins each containing a pore.
• Ion selectivity in channel pores is based on size or charge.
• The absolute refractory period means ion channels are inactivated after usage to keep the flow of action potentials in one direction.
• Phases of the action potential:
  • 1. threshold
  • 2. rising phase (inward Na+ current)
  • 3. overshoot
  • 4. falling phase (outward K+ current)
  • 5. undershoot
  • 6. absolute refractory period
  • 7. relative refractory period
• The oscilloscope is used to study action potentials and graphically displays voltages.
• Membrane potassium current will flow only if Vm does not equal Ek.
• Electrical conductance (gk) is proportional to the number of open potassium channels.
• Orthodromic action potential travels in one direction (down the axon), while antidromic action potential travels backward (experimental).
• Typical conduction velocity is 10 m/sec.
• A typical action potential length is ~2msec.
• Factors influencing conduction velocity include the spread of action potential along the membrane, the path of positive charge, and axonal excitability.
• A alpha nerves carry motor impulses & muscular proprioception, A beta nerves carry sensory (touch) impulses, A delta nerves carry pain and temperature impulses, and C nerves carry pain and temperature impulses.
• Myelin is layered around the axon to increase current flow and stops constant exchange of ions with the environment.
• The node of Ranvier is the gap in the myelin sheath for ion channels.
• The spike initiation zone includes sensory nerve endings and the axon hillock.
• Hodgkin and Huxley used the giant squid axon to test how nerve impulses traveled along the axon, determining that axon firing is electrochemical, involving sodium entering the axon and potassium leaving it.
• Patch clamping measures the current flowing through single ion channels.
• Toxins that poison ion channels evolved in several organisms as mechanisms for self-defense/capturing prey.
• Optogenetics uses light stimulation and genetics to manipulate the activity of individual neurons.
• Channelopathies are diseases and disorders that are the result of ion channel dysfunction.
• Tetrodotoxin blocks Na+ channels, is produced by pufferfish, and causes paralysis.
• Saxitoxin blocks Na+ channels, is found in algae that produces red tide (dinoflagellates), and causes paralysis.
• µ-conotoxins blocks Na+ channels and are produced by cones snails.
• Alpha toxins prolong action potential by slowing inactivation of Na+ channels and are produced by scorpions.
• Beta toxins shift voltage dependence of Na+ channels and are produced by scorpions.
• Batrachotoxin shifts voltage dependence of Na+ channels, prolongs action potential by slowing inactivation of Na+ channels, and are produced by species of frog.
• Toxins produced by plants include aconitine (buttercups), veratridine (lilies), and pyrethrins (chrysanthemums and rhododendrons).
• Synaptic transmission is the transfer of information at the synapse, playing a role in all the operations of the nervous system, and can be chemical or electrical.
• Charles Sherrington discovered the synapse in 1897, Otto Loewi discovered acetylcholine/support for chemical synapses in 1921, and Furshpan and Potter proved the existence of electrical synapse in crayfish in late 1950's.
• Information flow is generally from the presynaptic neuron to the target cell (postsynaptic neuron).
• An axodendritic synapse is axon to dendrite, axosomatic is axon to cell body, axoaxonic is axon to axon, axospinous is axon to dendritic spine, and dendrodendritic is dendrite to dendrite.
• Gray's type I synapse has an asymmetrical membrane, more proteins on the postsynaptic neuron, and is usually excitatory, while Gray's type II synapse has a symmetrical membrane and is usually inhibitory.
• The Neuromuscular Junction (NMJ) exists outside of the CNS, studies provided info about synaptic transmission, and a synapse occurs on muscle using acetylcholine.
• Chemical synapses use neurotransmitters and their receptors, are Ca2+-dependent, unidirectional, and slower.
• Electrical synapses use gap junctions (connexon proteins) as ion channels, are bidirectional, and faster.
• Signaling at electrical synapses involves gap junctions and connexins, with instant communication.
• The generation of action potentials in one neuron results in the synchronized firing of action potentials in the adjacent neuron (instant communication).
• Connexins are subunits that form ion channels.
• Signaling at a chemical synapse involves electrical (action potential in presynaptic neuron), chemical (neurotransmitter diffusing across the synaptic cleft), and electrical (action potential in postsynaptic neuron) steps.
• Presynaptic structures:
  • Filamentous structures help guide vesicles to active zone.
  • Several pools of vesicles exist: only those at the active zone are ready for exocytosis.
• Postsynaptic structures/postsynaptic densities helps anchor postsynaptic receptors in postsynaptic membrane, prevents lateral diffusion of receptors, and contains many proteins involved in plasticity-dependent processes.
• Chemical transmission requires synthesizing and packaging neurotransmitter (prepare), causing the vesicles to spill their contents into the synaptic cleft (release), producing an electrical or biochemical response to neurotransmitter in the postsynaptic neuron (respond), and removing neurotransmitter from the synaptic cleft (stop).
• Neurotransmitter categories: amino acids, amines, and peptides.
• Amino acids are small organic molecules stored in vesicles (examples: glutamate, glycine, GABA), amines are small organic molecules stored in vesicles (examples: dopamine, acetylcholine, histamine), and peptides are short amino acid chains (proteins), stored in secretory granules (examples: dynorphin, enkephalins).
• Mechanisms of Neurotransmitter Release:
  • The process of exocytosis is stimulated by intracellular calcium [Ca2+].
  • Proteins alter conformation—activated.
  • Vesicle membrane incorporated into presynaptic membrane.
  • Neurotransmitter released into the cleft.
  • Vesicle membrane recovered by endocytosis.
• Molecular mechanisms of synaptic vesicle exocytosis:
  • Synapsin: mobilization
  • SNAPs: priming
  • NSFs: priming
  • SNAREs: docking
• Types of neurotransmitter receptors:
  • Ligand-gated ion channels (transmitter-gated ion channels)
  • Metabotropic receptors (g-protein-coupled receptors)
• Ligand-gated ion channels are ionotropic receptors, are fast (postsynaptic potentials responses range 1-2 msec after an action potential reaches the presynaptic terminal).
• Metabotropic receptors are G-protein-coupled receptors, are slow (postsynaptic potentials responses range: hundreds of msec to 1-2 minutes), and have a cascade of phosphorylation events and second-messenger production.
• Excitatory Postsynaptic Potential (EPSP) is a transient postsynaptic membrane depolarization caused by presynaptic release of neurotransmitter, permeable to both Na+ and K+, and brings the membrane closer to threshold.
• Inhibitory Postsynaptic Potential (IPSP) is a transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of neurotransmitter, permeable to Cl-, and hyperpolarizes the membrane.
• Autoreceptors are commonly found in the membrane of the presynaptic axon terminal, consequences of activating autoreceptors vary (common effect is inhibition of neurotransmitter release), and appears to function as a sort of safety valve.
• Neurotransmitter recovery and degradation occurs by diffusion of transmitter molecules away from the synapse.
• Reuptake: Neurotransmitter re-enters presynaptic axon terminal reuptake
• Enzymatic destruction inside terminal cytosol or synaptic cleft
• Desensitization: for example, AChE cuts Ach to render it inactive
• Neuropharmacology is the study of effects of drugs on nervous system tissue.
• Receptor antagonists inhibits neurotransmitter receptors (ie: curare) while receptor agonists mimic actions of naturally occurring neurotransmitters (ie: nicotine).
• Defective neurotransmission is the root cause of neurological and psychiatric disorders.
• Synaptic integration:
  • Process by which multiple synaptic potentials combine within one postsynaptic neuron
  • Most CNS neurons receive thousands of synaptic inputs
  • Neural computation Process of endocytosing a vesicle:
  • 1. adaptor proteins connect clathrin proteins to the vesicle membrane
  • 2. the clathrin assemble into a sphere, bringing the membrane with it
  • 3. dynamin ring forms and pinches off the lipid stalk
  • 4. the coated vesicle is translocated via actin
  • 5. Hsc70, auxilin, and synaptojanin uncoat the vesicle
  • 6. actin carries vesicle away
• Quantal analysis of EPSPs:
  • The number of transmitter molecules in a single synaptic vesicle and the number of postsynaptic receptors available at the synapse
  • A method of comparing the amplitudes of miniature and evoked PSP's
• Synaptic vesicles are elementary units of synaptic transmission.
• Quantum definition: a discrete quantity of energy proportional in magnitude to the frequency of the radiation it represents.
• Synaptic transmission in the absence of stimulation means some vesicles are still released, but the signals don't necessarily reach threshold in the postsynaptic neuron (miniature postsynaptic potential).
• One vesicle that is released = 1 mini.
• Integration (EPSP): EPSPs are added together to produce significant postsynaptic depolarization.
• Spatial summation (EPSP): EPSPs are generated simultaneously at different sites.
• Temporal summation (EPSP): EPSPs are generated at the same synapse in rapid succession.
• Inhibition (action potential):
  • Take membrane potential away from action potential threshold
  • Exert powerful control over neuron output
  • Membrane potential less negative than −65 mV = hyperpolarizing IPSP
• Shunting inhibition: synapse inhibits current flow from soma to axon hillock.
• Excitatory vs. inhibitory synapses bind different neurotransmitters, allowing different ions to pass through channels.
• Modulation:
  • Synaptic transmission that modifies effectiveness of EPSPs generated by other synapses with transmitter
  • Gated ion channels
  • Activation can close ion channels or open K+ channels
  • Activating NE β receptor

Explore the historical perspectives on the brain's function, from ancient beliefs to Galen's discoveries. Understand synaptic transmission, including the roles of neurotransmitters and toxins. Identify the characteristics of Gray's type I and II synapses.