Summary

Synaptic Transmission Is Usually Chemical but Can Be Electrical

• Most synapses are chemical; some are electrical. Electrical synapses are very fast and usually are bidirectional. Gap junctions are the anatomical basis of electrical synapses; they contain connexons that allow current to flow directly between the cells, electrically coupling them.
• Chemical synapses are unidirectional, with a presynaptic neuron that releases neurotransmitter when stimulated, and a postsynaptic neuron (or effector) that bears receptor molecules to which the neurotransmitter binds.
• Neurotransmitter receptors may directly open their own ion channels; or they may act indirectly through a signal transduction cascade that involves second messengers, to open, close, or change ion channels that are separate molecules.
• Electrical synapses mediate fast, synchronizing actions of neurons. Chemical synapses integrate neuronal functions, by fast (ionotropic) excitation and inhibition, or by slow (metabotropic) modulation of neuronal and synaptic properties.

Synaptic Potentials Control Neuronal Excitability

• Most synapses in nervous systems are chemical synapses that mediate fast excitation and inhibition. Neurotransmitters act at receptors to open ion channels, to depolarize (EPSP) or hyperpolarize (IPSP) the postsynaptic neuron.
• EPSPs and IPSPs summate, so the membrane potential of the postsynaptic neuron is a moment-to-moment integral of synaptic input.
• Postsynaptic potentials are graded and spread passively to the axon initial segment (the site of action-potential initiation). Therefore more-distant synapses may have smaller effects on the neuron’s output.

Fast Chemical Synaptic Actions Are Exemplified by the Vertebrate Neuromuscular Junction

• At the vertebrate skeletal neuromuscular junction, the neurotransmitter is acetylcholine. When stimulated, the presynaptic axon terminal releases acetylcholine, which diffuses to postsynaptic receptors.
• Acetylcholine binding to its receptors opens ion channels to increase permeability to both Na⁺ and K⁺ ions. The resulting Na⁺ and K⁺ currents drive the membrane toward a value (E_EPSP) that is more depolarized than the threshold of the muscle fiber. At the neuromuscular junction, the amplitude of the EPSP is sufficient to exceed threshold and triggers a muscle fiber action potential.
• The EPSP itself is a nonregenerative, nonpropagated local response because the neurotransmitter-dependent permeability changes are not voltage-dependent.
• Fast excitatory synapses in CNSs work by mechanisms similar to those at neuromuscular junctions. Neurotransmitter-gated ion channels increase membrane permeability to Na⁺ and K⁺ ions to produce depolarizing EPSPs.
• Neuronal EPSPs are much smaller than neuromuscular EPSPs because at neural synapses the postsynaptic membrane encompasses a small area that has a small number of receptor molecules, and the presynaptic axon releases less neurotransmitter, activating fewer postsynaptic receptors.
• Fast synaptic inhibition results from the opening of ion channels to increase permeability to chloride. E_Cl is commonly at a hyperpolarized value relative to the resting potential, leading to a hyperpolarizing IPSP.
• CNS excitatory and inhibitory synapses often have characteristic differences in their appearance in electron micrographs of the vertebrate CNS.

Presynaptic Neurons Release Neurotransmitter Molecules in Quantal Packets

• Small-molecule neurotransmitters are synthesized predominantly at axon terminals and are transported into synaptic vesicles.
• Neurotransmitters are released by presynaptic depolarization, which opens voltage-gated Ca²⁺ channels at active zones. Calcium ions trigger neurotransmitter release.
• Neurotransmitter is released in quantal packets, several thousand molecules at a time. Each quantum corresponds to a synaptic vesicle.
• Synaptic vesicles fuse with the presynaptic membrane to release their transmitter contents by exocytosis. Vesicular membranes are retrieved, refilled with neurotransmitter, and recycled.
• Specific proteins associated with synaptic vesicles play different roles in vesicular targeting, docking, fusion, and retrieval.

Neurotransmitters Are of Two General Kinds

• Neurotransmitters can be small molecules or peptides. Perhaps a dozen small-molecule neurotransmitters and several dozen peptide neurotransmitters have been identified.
• A neuron can be identified by its characteristic neurotransmitter, but a single neuron may produce and release more than one neurotransmitter.
• For any neurotransmitter there are several receptors. Different kinds of receptors for a transmitter may coexist in the same organism and the same neuron.
• Most fast synapses in CNSs employ glutamate for EPSPs and GABA or glycine for IPSPs.
• Many receptors for small-molecule neurotransmitters, and probably for all peptides, act metabotropically and mediate slow synaptic potentials and modulatory responses.
• Peptides are synthesized in the neuronal cell body and transported down the axon packed in vesicles, unlike small-molecule transmitters, which are synthesized locally in axon terminals.
• The synaptic action of small-molecule neurotransmitters is terminated by reuptake or by enzymatic destruction.

Postsynaptic Receptors for Fast Ionotropic Actions: Ligand-Gated Channels

• The receptors that produce fast PSPs are ligand-gated channels. They are receptor–channels because the same molecule is both the receptor and the ion channel.
• The nicotinic acetylcholine receptor of the neuromuscular junction is the model ligand-gated channel. It contains five homologous subunits that surround a central ion channel that opens to allow Na⁺ and K⁺ ions to flow across the membrane.
• A ligand-gated channel opens briefly in response to binding two molecules of neurotransmitter, contributing to the synaptic current that produces a PSP.

Postsynaptic Receptors for Slow, Metabotropic Actions: G Protein–Coupled Receptors

• Many neurotransmitter receptors act via second messengers, triggering metabolic cascades in postsynaptic neurons. These metabotropic receptor effects are often slow and long-lasting.
• G protein–coupled receptors (GPCRs) are the major receptors of metabotropic synapses. All GPCRs have seven membrane-spanning segments, and all are evolutionarily related.
• GPCRs act via G proteins. A G protein has three subunits; normally the α subunit becomes activated when it dissociates from the regulatory β and γ subunits.
• An activated G protein activates an intracellular effector, usually to produce an intercellular second messenger.
• Second messengers of importance in metabotropic synapses include cyclic AMP, the membrane phospholipid derivatives DAG and IP₃, and Ca²⁺ ions.
• Most second messengers activate protein kinases, which phosphorylate proteins such as ion channels and change their activity.
• G proteins can activate ion channels directly.
• Metabotropic receptors play roles in slow synaptic potentials in which permeability to ions decreases, and in presynaptic inhibition.

Synaptic Plasticity: Synapses Change Properties with Time and Activity

• Neuronal stimulation that increases the rate of neurotransmitter release also increases rates of neurotransmitter resynthesis. The homeostatic mechanisms of this regulation involve both substrate availability and more complex mechanisms.
• With a train of presynaptic action potentials, the amplitudes of the resultant postsynaptic potentials may increase (facilitation) or decrease (antifacilitation). Thus the synaptic transfer of information depends on its history.
• The synaptic bases of behavioral habituation, sensitization, and classical conditioning in Aplysia depend on second messenger–mediated control of the amount of neurotransmitter released at CNS synapses.
• Hippocampal long-term potentiation (LTP) is a long-lasting change in synaptic properties related to learning and memory. The induction of LTP depends on NMDA receptors that respond to both glutamate neurotransmitter and postsynaptic depolarization, to allow Ca²⁺ entry into the postsynaptic cell.
• LTP is maintained by means of Ca²⁺-dependent second-messenger pathways that make the postsynaptic cell more sensitive to glutamate neurotransmitter. Insertion of AMPA receptors into the postsynaptic membrane increases the amplitude of the postsynaptic response, and occurs along with expansion of the area of dendritic spines.
• Studies that manipulate the expression of critical genes in the LTP metabolic pathway significantly affect learning and memory in mice.

Copyright 2016 Sinauer Associates