chapter 8

Synapses and Synaptic Transmission

• Electrical Synapses:

  • Direct communication via gap junctions.
  • Rapid communication due to electrical coupling.
  • Local current from action potential flows directly to another cell.
  • Found in smooth and cardiac muscle, CNS neurons, and between CNS neurons and glial cells.
  • Synchronizes activity, e.g., neural control of inspiration.

• Chemical Synapses:

  • Communication via neurotransmitters.
  • Neurotransmitters released from presynaptic axon terminal diffuse to postsynaptic neuron.
  • Initiates membrane potential change in postsynaptic neuron.
  • Allows integration of multiple signals on one neuron.

Types of Chemical Synapses

• Axodendritic: Axon terminal synapses on dendrites.
• Axosomatic: Axon terminal synapses on cell body (soma).
• Axoaxonic: Axon terminal synapses on another axon terminal; regulates activity at specific synapses.
• Synapses occur between neurons and effector organs (muscle or gland).

Synaptic Communication and Graded Potentials

• Synaptic activity affects the likelihood of postsynaptic neuron firing an action potential.
• Excitatory Synapses:
  • Membrane potential moves closer to threshold (e.g., -55 mV).
• Inhibitory Synapses:
  • Membrane potential moves further from threshold or stabilizes at resting value.

Synaptic Transmission Mechanism

• Action potential reaches axon terminals of presynaptic neuron.
• Voltage-gated calcium channels open, allowing $Ca^{2+}$ to enter the axon terminal.
• $Ca^{2+}$ triggers neurotransmitter release.
• Neurotransmitter diffuses across synaptic cleft and binds to receptors on postsynaptic membrane.
• Ligand-gated channels open, causing a graded potential.
• The axon hillock integrates all incoming signals.
  • If the membrane potential at the axon hillock reaches threshold (-55 mV), an action potential is initiated in the postsynaptic neuron.
• Action potential propagates down the axon via sequential opening of voltage-gated sodium and potassium channels.

Anatomy of Synapses

• Neurotransmitters are stored in synaptic vesicles in the axon terminal.
• Neurotransmitter synthesis occurs in the axon terminal.
• Action potential triggers neurotransmitter release into the synaptic cleft.
• Neurotransmitter binds to receptors on the postsynaptic membrane, initiating a signal transduction mechanism.

Neurotransmitter Release

• Axon terminals have voltage-gated calcium ion channels.
• Depolarization stimulates voltage-gated calcium channels to open, allowing $Ca^{2+}$ to enter.
• Increase in cytosolic $Ca^{2+}$ concentration triggers exocytosis and neurotransmitter release.
• The amount of neurotransmitter released depends on the amount of $Ca^{2+}$ that enters the axon terminal.

Influence of Calcium and Action Potential Frequency

• More $Ca^{2+}$ entry leads to more neurotransmitter release, resulting in a stronger graded potential in the postsynaptic neuron.
• High action potential frequency causes more $Ca^{2+}$ release and a stronger effect on the postsynaptic neuron.
• Axoaxonic synapses can modulate $Ca^{2+}$ entry into the axon terminal.

Postsynaptic Cell Response

• Neurotransmitters bind to ligand-gated channels or G protein-coupled receptors.
• Ligand-gated channels produce a fast response by rapidly altering the membrane potential.
• G protein-coupled receptors mediate slower responses by affecting ion channels or initiating second messenger systems.
• The change in membrane potential can be either excitatory (depolarizing) or inhibitory (hyperpolarizing).

Excitatory Synapses (EPSP)

• Excitatory postsynaptic potentials (EPSPs) are depolarizing graded potentials.
• Move the postsynaptic neuron closer to the threshold for generating an action potential.
• More neurotransmitter released leads to a stronger depolarizing graded potential.

Fast EPSPs

• The receptor is the same protein as the ion channel, permeable to both sodium and potassium ions.
• More sodium ions rush into the cell than potassium ions leave, resulting in depolarization.

Slow EPSPs

• Involve G protein-coupled receptors.
• Neurotransmitter binding initiates the production of a second messenger (e.g., cyclic AMP).
• Cyclic AMP activates protein kinase A, which phosphorylates and closes potassium channels.
• Slower to develop but last longer (seconds to hours).
• $cAMP$ concentration at is elevated in the cell

Inhibitory Synapses (IPSP)

• Inhibitory postsynaptic potentials (IPSPs) are either hyperpolarizing graded potentials or stabilize the membrane potential.
• Make the postsynaptic neuron less likely to produce an action potential.
• Involve opening of potassium or chloride ion channels.

Fast IPSPs

• Ligand-gated potassium channels open, allowing potassium to exit the cell and causing hyperpolarization.
• Chloride ion channels opening can cause hyperpolarization or stabilize the membrane potential.

Signal Transduction Mechanisms

• Ionotropic Receptors: Ligand-gated ion channels that produce fast responses.
• Metabotropic Receptors: G protein-coupled receptors that mediate slower responses and can have longer effects.
  • G proteins can open or close ion channels.
  • Second messenger systems can be activated or inhibited, leading to modification of proteins or protein synthesis.

Ionotropic Receptors

• Neurotransmitter binding causes direct opening of the ion channel.
• Ion movement depends on the specific channel and electrochemical gradient.

Metabotropic Receptors

• Direct Coupling: G protein subunit directly influences the state of an ion channel (opening or closing).
• Second Messenger System:
  • G protein interacts with an enzyme to produce a second messenger.
  • Second messenger affects ion channels or cellular responses.
  • Can involve phosphorylation of proteins, affecting transcription factors, and influencing protein synthesis.

Effects of Neurotransmitters

• Neurotransmitter binding to ligand-gated ion channels leads to fast, short-acting changes.
  • Opening sodium channels: EPSP (depolarization).
  • Opening potassium or chloride channels: IPSP (hyperpolarization or stabilization).
• Neurotransmitter binding to G protein-coupled receptors:
  • Direct coupling: G protein alters the state of an ion channel.
  • Second messenger system: influences ion channels or modifies proteins and regulates protein synthesis.

Divergence and Convergence

• Divergence: A single presynaptic cell affects multiple postsynaptic cells.
• Convergence: Hundreds to thousands of presynaptic cells affect a single postsynaptic cell.
  • One synapse alone is usually not enough to determine whether an action potential will be generated.

Neural Integration (Synaptic Integration)

• Summation of input to a neuron determines whether it will fire an action potential.
• The axon hillock acts as an integrating center.
• An action potential is triggered if the membrane potential at the axon hillock is depolarized to threshold.
• The activity of a neuron depends on the additive effects of all graded potentials at any given time.

Summation

• Postsynaptic potentials are added together to affect the membrane potential in the postsynaptic neuron.
• Determines the membrane potential at the axon hillock and action potential frequency.
• Graded potentials last longer than action potentials, allowing for summation.
• More calcium in axon terminals leads to more neurotransmitter release, affecting ion channel activity and permeability.
• Metabotropic receptors can cause postsynaptic potentials to persist even after the neurotransmitter is cleared.

Temporal Summation

• Postsynaptic potentials are generated in rapid succession at one synapse.
• Signals that are normally subthreshold can reach threshold when they overlap in time.

Spatial Summation

• Postsynaptic potentials arise from different synapses but are generated around the same time.
• The axon hillock integrates inputs from different synapses at relatively the same time.
• An IPSP can cancel out an EPSP.

Frequency Coding

• Summation of postsynaptic potentials affects the degree of depolarization at the axon hillock.
• As long as depolarization happens to threshold at the axon hillock, the axon can continue to generate action potentials.
• The frequency of action potentials communicates different levels of stimulus intensity.

Presynaptic Modulation (Axoaxonic Synapses)

• Axon terminal affects another axon terminal, regulating neurotransmitter release.
• Also sometimes called modulatory synapses
• Neurotransmitter binding causes a change in the amount of calcium ions that enter the axon terminal.
• Presynaptic Facilitation: Enhances the amount of neurotransmitter released.
• Presynaptic Inhibition: Decreases the amount of neurotransmitter released.
• No electrical signals are generated; it simply affects the amount of calcium entry.
• Selectively controls one specific input to a postsynaptic neuron.

Neurotransmitters

• Influence ion channels, affecting membrane potential and leading to excitation or inhibition.
• Can have longer-lasting effects through metabotropic receptors.
• Involved in metabolic processes, altering enzyme activities and protein synthesis.

Acetylcholine (ACh)

• Most abundant neurotransmitter in the peripheral nervous system (somatic and autonomic branches).
• Neurons that release acetylcholine are called cholinergic neurons.
• Involved in opening ion channels.
• Synthesized by choline acetyltransferase in the axon terminal.
  • $Choline + Acetyl coA \stackrel{Choline Acetyltransferase}{\longrightarrow} Acetylcholine + CoA$ synthesized in axon terminal
• Broken down by acetylcholinesterase in the synaptic cleft.
  • $Acetylcholine + H_2O \stackrel{Acetylcholinesterase}{\longrightarrow} Acetate + Choline$ degraded in synaptic cleft
• Choline is recycled back into the axon terminal.

Cholinergic Receptors

• Two main types:
  • Nicotinic Cholinergic Receptors
  • Muscarinic Cholinergic Receptors
• Different neurons have different types of receptors for specific neurotransmitters.

Nicotinic Cholinergic Receptors

• Ionotropic (fast ligand-gated channels).
• Two binding sites for acetylcholine.
• Binding opens ion channel permeable to sodium and potassium ions.
• More sodium rushes in, causing depolarization (EPSP).

Muscarinic Cholinergic Receptors

• Metabotropic (GPCRs).
• Binding one acetylcholine affects a G protein.
• Can affect ion channels or involve second messenger systems.
• Subclasses (M1, M2, M3) with different effects.
• (M2, beta-gamma complex opens $K^+$ channels = hyperpolarization or IPSP)
• (M3 alpha subunit can close $K^+$ and the activation of phospholipase C can open $Ca^{2+}$ channels =EPSP)

Biogenic Amines

• Synthesized from amino acids; have an amine group.

Serotonin

• Synthesized from tryptophan.
• Important in the central nervous system, especially the brainstem and midbrain.
• Involved in sleep and emotion regulation.

Histamine

• Derived from histidine.
• Used in the central nervous system, particularly in the hypothalamus.

Catecholamines

• Derived from tyrosine.
  • Dopamine
  • Norepinephrine (noradrenaline)
  • Epinephrine (adrenaline)
• Act through G protein-coupled receptors (metabotropic).
• Norepinephrine: Central nervous system and peripheral nervous system.
• Epinephrine: Hormone secreted by the adrenal medulla.
• Often function as autocrine signals, modulating their own release.

Adrenergic Receptors

• Receptors for norepinephrine and epinephrine.
• G protein-coupled receptors (metabotropic).
  • Alpha adrenergic receptors
  • Beta adrenergic receptors
• Norepinephrine binds to alpha and beta-one receptors with higher affinity.
• Beta-two receptors have a high affinity for epinephrine.
• Found in the central nervous system and effector organs of the sympathetic branch of the autonomic nervous system.
• Catecholamines do not directly cause ion channels to open, resulting in slower responses mediated through G proteins.
• Cyclic AMP is a common second messenger.
• Degradation is accomplished by:
  • Monoamine oxidase (MAO)
  • Catechol O-methyltransferase (COMT)
• Monoamine oxidase inhibitors (MAOIs) are a major class of antidepressants that increases biogenic amine concentration, which are often deficient in clinical depression.

Amino Acid Neurotransmitters

• Most prevalent class of neurotransmitters in the central nervous system.
  • Glutamate and Aspartate (excitatory)
  • Glycine and GABA (inhibitory)

Glutamate

• Primary excitatory neurotransmitter in the central nervous system.

• Released at half of our excitatory synapses.

• Three receptor types:

  • AMPA receptors: Depolarizing graded potentials (EPSPs) through opening of sodium and potassium channels with more sodium coming into the cells
  • Kinite receptors: Depolarizing graded potentials (EPSPs) through opening of sodium and potassium channelswith more sodium coming into the cells
  • NMDA receptors:Inotropic, opening of calcium channels.

• Important in Long-Term Potentiation (LTP) which is involved in learning and memory. Frequent activity causes lasting changes to make connections stronger. Cooperating with multiple receptor sites, AMPA anNMDA which activates a paracrine chemical messenger that then releases more neurotransmitter. Calcium ions activate protein kinases, affecting genetic expression and protein synthesis, strengthening the synapse. After LTP, any action potential will cause greater depolarization.

GABA

• Modified glutamate; the most common inhibitory neurotransmitter in the central nervous system.

• A third of our inhibitory neurons in the central nervous system uses them

• Multiple receptor types:

  • GABA A receptors: Ionotropic, ligand-gated chloride ion channels causing an IPSP.
  • GABA C receptors: Visual information in the retina through ionotropic, ligand-gated chloride ion channels causing an IPSP.
  • GABA b class of receptors: Metabotropic (GPCRs), opening potassium ion channels and causing a slower IPSP.

• Depressing central nervous activity: Alcohol and drugs (treat anxiety).

Glycine

• Released from inhibitory interneurons in the spinal cord and brainstem.
• Ionotropic, ligand-gated chloride ion channels, causing an IPSP.
• Regulation of skeletal muscle movement, allowing relaxation of antagonistic muscles during contraction.

Neuropeptides

• Shorter chains of amino acids.
• Act on metabotropic receptors.
• Co-secreted with a neurotransmitter and modulates the response of the postsynaptic neuron to the other neurotransmitter.
• Often also act on hormones or Paracrine signals.
• Examples: vasopressin, TRH, oxytocin.

Nitric Oxide

• Gas that functions as a neurotransmitter.
• Produced by certain neurons in the central nervous system and the peripheral nervous system.
• Synthesized in the enzymes of the axon terminals in response to calcium entering into the axon terminals.
• Diffuses into the intracellular fluid of the other neurons.
• Example: Activates guanylyl cyclase, increasing the production of the second messenger cyclic GMP.

Synaptic Communication and Drugs

• Changes to the events at synapses and the ways that drugs can have an effect on communication.
• Increases or blocks neurotransmitter activity; alters enzyme degradation or receptor amount.