Fundamentals of the Nervous System and Nervous Tissue

The Synapse

• The nervous system relies on information flow from neuron to neuron.

• Neurons are functionally connected by synapses. These are junctions that mediate information transfer:

  • From one neuron to another neuron.

  • From one neuron to an effector cell.

• Presynaptic neuron: Neuron conducting impulses toward the synapse (sends information).

• Postsynaptic neuron: Neuron transmitting an electrical signal away from the synapse (receives information).

  • In the PNS, this may be a neuron, muscle cell, or gland cell.

  • Most neurons function as both presynaptic and postsynaptic.

Synaptic Connections

• Axodendritic: Between axon terminals of one neuron and dendrites of others.

• Axosomatic: Between axon terminals of one neuron and the soma (cell body) of others.

• Less common connections include:

  • Axoaxonal: Axon to axon.

  • Dendrodendritic: Dendrite to dendrite.

  • Somatodendritic: Dendrite to soma.

• Two main types of synapses:

  • Chemical synapse.

  • Electrical synapse.

Chemical Synapses

• Most common type of synapse.

• Specialized for the release and reception of chemical neurotransmitters.

• Typically composed of two parts:

  • Axon terminal of presynaptic neuron: Contains synaptic vesicles filled with neurotransmitter.

  • Receptor region on the postsynaptic neuron's membrane: Receives neurotransmitter (usually on a dendrite or cell body).

  • These two parts are separated by a fluid-filled synaptic cleft.

• The electrical impulse is changed to a chemical signal across the synapse, then back into an electrical signal.

Transmission Across the Synaptic Cleft

• The synaptic cleft prevents nerve impulses from directly passing from one neuron to the next.

• Transmission is a chemical event involving the release, diffusion, and receptor binding of neurotransmitters.

• Ensures unidirectional communication between neurons.

Information Transfer Across Chemical Synapses - Six Steps

1. Action Potential (AP) Arrives: The AP arrives at the axon terminal of the presynaptic neuron.

2. Calcium Channels Open: Voltage-gated Ca^{2+} channels open, and Ca^{2+} enters the axon terminal.

   • Ca^{2+} flows down its electrochemical gradient from the extracellular fluid (ECF) into the axon terminal.

3. Neurotransmitter Release: Ca^{2+} entry causes synaptic vesicles to release neurotransmitter.

   • Ca^{2+} causes synaptotagmin protein to interact with SNARE proteins, controlling the fusion of synaptic vesicles with the axon membrane.

   • Fusion results in exocytosis of neurotransmitter into the synaptic cleft.

   • The higher the impulse frequency, the more vesicles exocytose, leading to a greater effect on the postsynaptic cell.

4. Neurotransmitter Diffusion and Binding: The neurotransmitter diffuses across the synaptic cleft and binds to specific receptors on the postsynaptic membrane.

   • Often, these receptors are chemically gated ion channels.

   • Binding of neurotransmitter opens ion channels, creating graded potentials.

   • Binding causes the receptor protein to change shape, opening ion channels.

     • This causes a graded potential in the postsynaptic cell.

     • Can be an excitatory or inhibitory event.

     • Some receptor proteins are also ion channels.

5. Termination of Neurotransmitter Effects: Neurotransmitter effects are terminated to regulate the graded potentials.

   • Within a few milliseconds, the neurotransmitter effect is terminated in one of three ways:

     • Reuptake by astrocytes or the axon terminal.

     • Degradation by enzymes.

     • Diffusion away from the synaptic cleft.

6. Synaptic Delay: The time needed for the neurotransmitter to be released, diffuse across the synapse, and bind to receptors.

   • Can take anywhere from 0.3 to 5.0 ms.

   • It's the rate-limiting step of neural transmission.

   • Transmission of an AP down the axon can be very quick, but the synapse slows transmission to the postsynaptic neuron significantly.

   • This delay is usually not noticeable because these processes are still very fast.

Electrical Synapses

• Less common than chemical synapses.

• Neurons are electrically coupled.

  • Joined by gap junctions that connect the cytoplasm of adjacent neurons.

• Communication is very rapid and can be unidirectional or bidirectional.

• Found in some brain regions responsible for eye movements or the hippocampus in areas involved in emotions and memory.

• Most abundant in embryonic nervous tissue.

Postsynaptic Potentials

• Neurotransmitter receptors cause graded potentials that vary in strength based on:

  • Amount of neurotransmitter released.

  • Time the neurotransmitter stays in the cleft.

• Depending on the effect of the chemical synapse, there are two types of postsynaptic potentials:

  • EPSP: Excitatory postsynaptic potential.

  • IPSP: Inhibitory postsynaptic potential.

Excitatory Synapses and EPSPs

• Neurotransmitter binding opens chemically gated channels.

  • Allows simultaneous flow of Na^{+} and K^{+} in opposite directions.

• Na^{+} influx is greater than K^{+} efflux, resulting in a local net graded potential depolarization called an excitatory postsynaptic potential (EPSP).

• EPSPs trigger an AP if the EPSP is of threshold strength.

  • Can spread to the axon hillock and trigger the opening of voltage-gated channels, causing an AP to be generated.

Inhibitory Synapses and IPSPs

• Neurotransmitter binding to the receptor opens chemically gated channels that allow the entrance/exit of ions that cause hyperpolarization.

  • Makes the postsynaptic membrane more permeable to K^{+} or Cl^{-}.

    • If K^{+} channels open, it moves out of the cell.

    • If Cl^{-} channels open, it moves into the cell.

  • Reduces the postsynaptic neuron’s ability to produce an action potential.

    • Moves the neuron farther away from the threshold (makes it more negative).

Integration and Modification of Synaptic Events

• Summation by the postsynaptic neuron:

  • A single EPSP cannot induce an AP, but EPSPs can summate (add together) to influence the postsynaptic neuron.

  • IPSPs can also summate.

  • Most neurons receive both excitatory and inhibitory inputs from thousands of other neurons.

    • Only if EPSPs predominate and bring to threshold will an AP be generated.

  • Two types of summation: temporal and spatial.

• Temporal Summation

  • One or more presynaptic neurons transmit impulses in rapid-fire order.

  • The first impulse produces an EPSP, and before it can dissipate, another EPSP is triggered, adding on top of the first impulse.

• Spatial Summation

  • The postsynaptic neuron is stimulated by a large number of terminals simultaneously.

  • Many receptors are activated, each producing EPSPs, which can then add together.

• Synaptic Potentiation

  • Repeated use of a synapse increases the ability of the presynaptic cell to excite the postsynaptic neuron.

    • Ca^{2+} concentration increases in the presynaptic terminal, causing the release of more neurotransmitter.

    • Leads to more EPSPs in the postsynaptic neuron.

  • Potentiation can cause Ca^{2+} voltage gates to open on the postsynaptic neuron.

    • Ca^{2+} activates kinase enzymes, leading to a more effective response to subsequent stimuli.

  • Long-term potentiation: Important for learning and memory.

• Presynaptic Inhibition

  • The release of excitatory neurotransmitter by one neuron is inhibited by another neuron via an axoaxonal synapse.

  • Less neurotransmitter is released, leading to smaller EPSPs.

Neurotransmitters

• The language of the nervous system.

• 50 or more neurotransmitters have been identified.

• Most neurons make two or more neurotransmitters.

  • Neurons can exert several influences.

  • Usually released at different stimulation frequencies.

• Classified by:

  • Chemical structure.

  • Function.

Classification of Neurotransmitters by Chemical Structure

• Acetylcholine (ACh)

  • First identified and best understood.

  • Released at neuromuscular junctions.

    • Also used by many ANS neurons and some CNS neurons.

  • Synthesized from acetic acid and choline by the enzyme choline acetyltransferase.

  • Degraded by the enzyme acetylcholinesterase (AChE).

• Biogenic Amines

  • Catecholamines

    • Dopamine, norepinephrine (NE), and epinephrine: made from the amino acid tyrosine.

  • Indolamines

    • Serotonin: made from the amino acid tryptophan.

    • Histamine: made from the amino acid histidine.

  • All widely used in the brain: play roles in emotional behaviors and the biological clock.

  • Used by some ANS motor neurons, especially NE.

  • Imbalances are associated with mental illness.

• Amino Acids

  • Amino acids make up all proteins; therefore, it's difficult to prove which are neurotransmitters.

  • Amino acids that are proven neurotransmitters:

    • Glutamate.

    • Aspartate.

    • Glycine.

    • GABA: gamma-aminobutyric acid.

• Peptides (Neuropeptides)

  • Strings of amino acids that have diverse functions.

    • Substance P: Mediator of pain signals.

    • Endorphins: Beta-endorphin, dynorphin, and enkephalins act as natural opiates, reducing pain perception.

    • Gut-brain peptides: Somatostatin and cholecystokinin play a role in regulating digestion.

• Purines

  • Monomers of nucleic acids that have an effect in both the CNS and PNS.

    • ATP, the energy molecule, is now considered a neurotransmitter.

    • Adenosine is a potent inhibitor in the brain.

      • Caffeine blocks adenosine receptors.

      • Can induce Ca^{2+} influx in astrocytes.

• Gases and Lipids

  • Gasotransmitters

    • Nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide gases (H_2S).

    • Bind with G protein-coupled receptors in the brain.

    • Lipid-soluble and synthesized on demand.

    • NO is involved in learning and the formation of new memories, as well as brain damage in stroke patients and smooth muscle relaxation in the intestine.

    • H_2S acts directly on ion channels to alter function.

  • Endocannabinoids

    • Act at the same receptors as THC (the active ingredient in marijuana).

    • Most common G protein-linked receptors in the brain.

    • Lipid-soluble and synthesized on demand.

    • Believed to be involved in learning and memory.

    • May be involved in neuronal development, controlling appetite, and suppressing nausea.

Neurotransmitter Functions

• Neurotransmitters exhibit a great diversity of functions.

• Functions can be grouped into two classifications:

  • Effects.

  • Actions.

Neurotransmitter Effects

• Excitatory Versus Inhibitory

  • Neurotransmitter effects can be excitatory (depolarizing) and/or inhibitory (hyperpolarizing).

  • The effect is determined by the receptor to which it binds.

    • GABA and glycine are usually inhibitory.

    • Glutamate is usually excitatory.

    • Acetylcholine and NE bind to at least two receptor types with opposite effects.

      • ACh is excitatory at neuromuscular junctions in skeletal muscle.

      • ACh is inhibitory in cardiac muscle.

Neurotransmitter Actions

• Direct Versus Indirect

  • Direct action: The neurotransmitter binds directly to and opens ion channels.

    • Promotes rapid responses by altering membrane potential.

    • Examples: ACh and amino acids.

  • Indirect action: The neurotransmitter acts through intracellular second messengers, usually G protein pathways.

    • Broader, longer-lasting effects similar to hormones.

    • Biogenic amines, neuropeptides, and dissolved gases.

• Neuromodulator

  • A chemical messenger released by a neuron that does not directly cause EPSPs or IPSPs but instead affects the strength of synaptic transmission.

    • May influence the synthesis, release, degradation, or reuptake of neurotransmitters.

    • May alter the sensitivity of the postsynaptic membrane to neurotransmitters.

    • May be released as a paracrine, meaning the effect is only local.

Channel-Linked Receptors

• Ligand-gated ion channels.

• Action is immediate and brief.

• Excitatory receptors are channels for small cations.

  • Na^{+} influx contributes most to depolarization.

• Inhibitory receptors allow Cl^{-} influx, causing hyperpolarization.

G Protein-Linked Receptors

• Responses are indirect, complex, slow, and often prolonged.

• Involve transmembrane protein complexes.

• Cause widespread metabolic changes.

• Examples:

  • Muscarinic ACh receptors.

  • Receptors that bind biogenic amines.

  • Receptors that bind neuropeptides.

• Mechanism:

  • The neurotransmitter binds to the G protein-linked receptor, activating the G protein.

  • The activated G protein controls the production of second messengers, such as cyclic AMP, cyclic GMP, diacylglycerol, or Ca^{2+}.

  • Second messengers can then:

    • Open or close ion channels.

    • Activate kinase enzymes.

    • Phosphorylate channel proteins.

    • Activate genes and induce protein synthesis.

Neural Integration

• Neural integration: neurons functioning together in groups.

• Groups contribute to broader neural functions.

• There are billions of neurons in the CNS.

• Must have integration so that the individual parts fuse to make a smoothly operating whole.

Organization of Neurons: Neuronal Pools

• Neuronal pool: Functional groups of neurons.

  • Integrate incoming information received from receptors or other neuronal pools.

  • Forward processed information to other destinations.

• Simple Neuronal Pool

  • A single presynaptic fiber branches and synapses with several neurons in the pool.

  • Discharge zone: Neurons closer to the incoming fiber are more likely to generate an impulse.

  • Facilitated zone: Neurons on the periphery of the pool are farther away from the incoming fiber; they are usually not excited to threshold unless stimulated by another source.

Patterns of Neural Processing

• Serial Processing

  • Input travels along one pathway to a specific destination.

    • One neuron stimulates the next one, which stimulates the next one, etc.

  • The system works in an all-or-none manner to produce a specific, anticipated response.

  • The best example of serial processing is a spinal reflex.

• Reflexes

  • Rapid, automatic responses to stimuli.

  • A particular stimulus always causes the same response.

  • Occur over pathways called reflex arcs that have five components:

    • Receptor.

    • Sensory neuron.

    • CNS integration center.

    • Motor neuron.

    • Effector.

• Parallel Processing

  • Input travels along several pathways.

  • Different parts of the circuitry deal simultaneously with the information.

    • One stimulus promotes numerous responses.

  • Important for higher-level mental functioning.

  • Example: A sensed smell may remind one of an odor and any associated experiences.

Types of Circuits

• Circuits: patterns of synaptic connections in neuronal pools.

• Four types of circuits:

  • Diverging.

  • Converging.

  • Reverberating.

  • Parallel after-discharge.

Developmental Aspects of Neurons

• The nervous system originates from the neural tube and neural crest formed from the ectoderm.

• The neural tube becomes the CNS.

  • Neuroepithelial cells of the neural tube proliferate into the number of cells needed for development.

  • Neuroblasts become amitotic and migrate.

  • Neuroblasts sprout axons to connect with targets and become neurons.

• Growth Cone

  • A prickly structure at the tip of an axon that allows it to interact with its environment via:

    • Cell surface adhesion proteins (laminin, integrin, and nerve cell adhesion molecules, or N-CAMs), which provide anchor points.

    • Neurotropins that attract or repel the growth cone.

    • Nerve growth factor (NGF), which keeps the neuroblast alive.

    • Filopodia are growth cone processes that follow signals toward the target.

• Once an axon finds its target, it must then find the right place to form a synapse.

  • Astrocytes provide physical support and the cholesterol needed for the construction of synapses.

• About two-thirds of neurons die before birth.

  • If axons do not form a synapse with their target, they are triggered to undergo apoptosis (programmed cell death).

  • Many other cells also undergo apoptosis during development.

• During childhood and adolescence, learning reinforces certain synapses and prunes away others.

  • Recent evidence suggests that genes that promote excessive synaptic pruning may predispose an individual to schizophrenia.

• Neurons are amitotic after birth; however, there are a few special neuronal populations that continue to divide.

  • Olfactory neurons and the hippocampus.