Synaptic Transmission and Electrical Synapses

• Synaptic transmission is how neurons transfer information at localized sites of apposition called synapses.
• Most synapses use adaptations of the secretory processes as the basis of chemically mediated signal transfer.

Electrical Synapses

• Electrical synapses involve current (and voltage changes) that spread passively from one neuron to another.
• Electrical synapses have a speed advantage over chemical synapses.
• Chemical synapses have more advantages and dominate signal transfer between neurons.

Gap Junctions

• Electrical synapses are based on gap junctions.
• At gap junctions the separation between adjoining neurons narrows, and the gap is spanned by pairs of channels.
• These channels provide a route for current to flow from one neuron to another.
• Each channel, called a connexon, is composed of six connexin molecules surrounding a central pore.
• The central pore is larger than that of typical ion channels, allowing ions and small molecules to pass through it.
• Current can generally pass equally well in either direction, so depolarization and hyperpolarization can spread from one neuron to another nearly instantaneously through gap junctions.
• Electrical signals do not change much and cannot play a large role in computational functions.
• Gap junctions spread electrical signals through networks of interconnected neurons, synchronizing the activity of groups of neurons; useful in minority of situations.
• Some neuron networks spread signals laterally over substantial distances; coupling by gap junctions allows them to function as an electrical syncytium.
• Retinal horizontal cells are electrically coupled, allowing information about illumination in one part of the retina to spread to others.
• Gap junctions provide a route for metabolic coupling between cells - an important signaling mechanism during development.
• Gap junctions between astrocytes allow metabolic substrates to move around within the CNS.
• Gap junctions can form between different parts of an individual cell allowing substances to take a short cut.
• Gap junctions especially apparent in myelinating glial cells, because they allow substances to move around without spiraling through myelin.

Control of Transmission at Electrical Synapses

• Connexons can switch between open and closed states.
• Intracellular parameters, such as pH, Ca++ concentration, and the voltage across a gap junction affect the probability of connexons being in one state or another.
• The degree of intercellular coupling is systemically managed; for instance, dopamine, released in the retina in response to light, culminates in phosphorylation of connexin and closes connexons.
• The extent to which information spreads laterally in the retina is different under light-adapted and dark-adapted conditions.

Chemical Synapses

• Chemical synapses allow more signaling flexibility.
• The basic elements of a chemical synapse are a presynaptic and postsynaptic element, separated by a synaptic cleft 10 nm or more across.
• Depolarization of the presynaptic element causes synaptic vesicles containing one or more neurotransmitters to release contents.
• Transmitter molecules then diffuse across the synaptic cleft, bind to neurotransmitter receptor molecules in the postsynaptic membrane, and directly or indirectly change the ionic permeability of the postsynaptic membrane.
• The nature and duration of the permeability change depend on the properties of the receptor, so the resulting potential change can be depolarizing (excitatory postsynaptic potential, or EPSP) or hyperpolarizing (inhibitory postsynaptic potential, or IPSP), fast or slow (Fig. 3-3).
• Depolarization of a presynaptic element results from action potentials spreading into it.
• At chemical synapses, the rate code embodied in a train of action potentials converts into graded potentials.

Synapse Structure and Transmissions

• Most presynaptic endings are parts of axons, synapsing on dendrites of other neurons as axon terminals or preterminal swellings as the axon passes by part of a dendrite.
• Any part of a neuron can be presynaptic to any other part (Fig. 3-4).
• Axon terminals make axodendritic synapses with dendrites and axoaxonic synapses with other axon terminals, and dendrites make dendrodendritic synapses with each other.
• Transmission at chemical synapses has five essential steps:
  • Synthesis of the neurotransmitter, either in presynaptic terminals or in neuronal cell bodies.
  • Concentration and packaging of neurotransmitter molecules in preparation for release.
  • Release of neurotransmitter into the synaptic cleft.
  • Binding of neurotransmitter by postsynaptic receptor molecules, triggering some effect in the postsynaptic ending.
  • Termination of neurotransmitter action, preparing the synapse for subsequent release of transmitter.

Packaging of Neurotransmitters

• More than 100 chemicals are used as neurotransmitters.
• Transmitters include small-molecule neurotransmitters such as amino acids and small amines, and neuropeptides up to a few dozen amino acids long.
• Both types are concentrated in membrane-bound synaptic vesicles, ready for release in response to presynaptic depolarization.
• Small-molecule neurotransmitters (e.g., glutamate, acetylcholine) are synthesized from locally available ingredients by cytoplasmic enzymes that arrive by slow axoplasmic transport.
• The transmitters are then loaded into small vesicles by specific transporters forming highly concentrated packets of neurotransmitter available for release.
• Neuropeptides are fragments of larger proteins synthesized in the cell body.
• The precursor proteins are packaged into somewhat larger vesicles that reach the synapse by fast axonal transport the precursors are processed into neuropeptide transmitters during the journey.
• Individual presynaptic endings commonly contain both small and large vesicles.

Release of Neurotransmitters

• Changes in intracellular Ca++ concentration initiate or modulate many cellular processes.
• A rise in presynaptic Ca++ concentration is the key signal initiating transmitter release.
• Presynaptic membranes contain voltage-gated Ca++ channels that open in response to depolarization; Ca++ influx results, because of both a voltage and a concentration gradient.
• Rise in presynaptic Ca++ concentration triggers an interaction between synaptic vesicle membrane proteins and presynaptic membrane proteins.
• Interaction results in fusion of synaptic vesicles with the surface membrane and discharge of contents.
• Subset of small synaptic vesicles forms clusters in active zones near presynaptic membrane, close to voltage-gated Ca++ channels, one or more vesicles of small-molecule transmitter release contents in response to small depolarizations or single action potentials (Fig. 3-6).
• Large synaptic vesicles are located farther away from active zones.
• The Ca++ concentration required to trigger fusion of these vesicles with the presynaptic membrane is achieved in response to large depolarizations or trains of action potentials (Fig. 3-7).
• Transmitter is stored in and released from vesicles of relatively uniform size, neurotransmitters are released as discrete packets, or quanta.
• Synaptic vesicle membranes retrieved by the synaptic terminal for reuse or degradation after fusion.
• Small vesicles are re-formed and refilled with transmitter multiple times (see Fig. 3-6), whereas the membranes of large vesicles are shipped back to the cell body for recycling or degradation (see Fig. 3-7).

Postsynaptic Receptors

• Neurotransmitter receptors fall into two categories (Fig. 3-8):
  • Ionotropic receptors
  • Metabotropic receptors
• Ionotropic receptors are ligand-gated ion channels, with a particular neurotransmitter serving as the ligand.
• Binding of transmitter increases the probability of the channel being open.
• Because of the coupling between transmitter binding and permeability changes, the postsynaptic potential mediated by an ionotropic receptor is relatively rapid (and brief).
• Its polarity depends on the ionic selectivity of the channel, predicted by the Goldman equation (see Eq. 2-3).
  • Closing K+ channels or opening Na+ channels causes an EPSP
  • Opening relatively nonselective monovalent cation channels, common at excitatory synapses, causes depolarization
  • Opening K+ channels or Cl- channels causes an IPSP
• Ionotropic receptors are assemblies of membrane-spanning subunits surrounding a central channel.
• Each assembly includes subunits of types, so numerous closely related receptors can be formed from different combinations of subunits.
• Nature and pharmacologists can develop selective agonists and antagonists binding to receptors in particular parts of the nervous system to mimic or block the effects of neurotransmitters.
• Metabotropic receptors also cause EPSPs and IPSPs, but indirectly.
• Metabotropic receptors affect the state of postsynaptic ion channels by way of second messengers; the "first messenger" is the neurotransmitter.
• Metabotropic receptors are transmembrane proteins, usually monomers, with an extracellular neurotransmitter binding site and an intracellular binding site for a G protein; therefore called G protein-coupled receptors.
• G proteins bind GDP and are inactive without neurotransmitter.
• Binding of transmitter enables G proteins to bind transiently to receptor, exchange GDP for GTP, dissociate into subunits.
• Depending on the specifics of a given G protein, the subunits participate in processes leading to postsynaptic voltage changes.
• Some bind directly to ion channels causing them to open or close; others stimulate or inhibit enzymes, such as adenylate cyclase, whose products may affect ion channels or other enzymes.
• Extra steps in processes mediated by metabotropic receptors provide amplification and modulation, resulting in postsynaptic potentials that develop more slowly and may be very long lasting.
• Metabotropic receptors are monomeric proteins and come in closely forms.
• Agonists and antagonists are selective for subsets of these receptors.

Postsynaptic Effects of Neurotransmitters

• Transmitters are excitatory or inhibitory.
• The effect of a transmitter at a given synapse is determined by the receptor to which it binds.
• Glutamate causes closing of nonselective cation channels (and IPSPs) at metabotropic receptors.
• Transmitters cause EPSPs at some synapses and IPSPs at others.

Termination of Neurotransmitter Action

• Processes try to remove transmitter molecules and "clear the decks" for subsequent releases (Fig. 3-9) at the same time neurotransmitters are binding to their receptors.
• Some neurotransmitter diffuses out of the synaptic cleft and is taken up by nearby cells or degraded enzymatically; principal route of removal for neuropeptides.
• Common mechanism: reuptake by specific transporters, either back into same presynaptic terminal or into glial processes surrounding the synapse.
• Exception: acetylcholine is hydrolyzed to acetate and choline by acetylcholinesterase, acetate is located adjacent to the synaptic cleft, and choline is transported back into the presynaptic terminal and used to make more acetylcholine.

Neurotransmitters

• Ten neurotransmitters are small, soluble molecules (see Table 3-1), interacting with both ionotropic and metabotropic receptors.
• Remaining transmitters: neuropeptides.

Small-Molecule Transmitters

• Principal small-molecule transmitters (see Table 3-1):
  • acetylcholine
  • few amino acids (glutamate, y-aminobutyric acid [GABA], and glycine)
  • diverse group of biogenic amines including (serotonin, histamine, and the catecholamines dopamine and norepinephrine).

Acetylcholine

• Acetylcholine (Table 3-2) is the major transmitter mediating fast excitatory transmission in the PNS.
• It acts at nicotinic receptors, Nicotinic receptors are on skeletal muscle fibers, where mediate neuromuscular transmission (no inhibitory synapses on vertebrate skeletal muscles), but also found on autonomic ganglion cells (see Chapter 18).
• Acetylcholine works through metabotropic muscarinic receptors (called this because muscarine, produced by Amanita muscaria, a poisonous mushroom, is a potent agonist at these sites).
• Muscarinic receptors are in the smooth muscles and glands targeted by autonomic axons, and they coexist with nicotinic receptors on autonomic ganglion cells.
• CNS role is important but more limited, involving muscarinic receptors.
• Interneurons in certain CNS nuclei are cholinergic and are a few collections of cholinergic neurons.

Amino Acids

• Glutamate (Table 3-3) is the major neurotransmitter mediating fast excitatory transmission throughout the CNS.
• Multiple ionotropic glutamate receptors, - most widespread being AMPA, NMDA receptors. AMPA receptors, like nicotinic acetylcholine receptors, are nonselective monovalent cation channels.
• NMDA receptors special properties voltage dependency + Ca++ permeability. Central pore of these receptors contains a Mg++ binding site that is occupied at normal resting potentials + occluding pore when glutamine binds.
• Depolarization of the postsynaptic membrane expels the Mg++ ion, causing current to flow through the pore.
• NMDA receptors allow Nat and K+ and also Ca++ to passage.
• Ca++ influx contributes to the EPSP and a second messenger, causing long term changes structural + functional for synapse. Act at metabotropic receptors, resulting IPSE and ESPS.
• GABA + glycine (Table 3-4) are major neurotransmitter in the CNS.
• Substantial roles spinal cord, but GABA as an Ionotripic receptor has multiple.

Biogenic Amines

• Amine neurotransmitters (see Table 3-4) like norepinephrine are autonomic synapses for the (PNS).
• CNS many brains have cell body cluster and discrete spots.
• Diffusely projecting make neutrons poorly suited for discrete information but well activity modulated.
• Changes attention for sleep-wake cycle (See chapter 19). w single exception, entirely through family of G-protein coupled receptors (Most metabotropic- one ligand-gated cannels).

Neuropeptides

• More than 50 different peptides, most are signaling molecules body and brain.
• Neuropeptides result slow release + structural slow changes through G-protien. Act alone with small molecules, instead neopetidide act only as a single transmitter, prolonged release with depolarization.

Control of Transmission at Chemical Synapses

• Need not be all-on-noting event.
• The steps are synthesizing, packing neuotransmitter.
• They provide changes for Ca+ influx binding and closes channels gives pre synaptics effect activity.
• Some change as a result for physiology the repeats leads build up over synapses.
• Not only releases neuropeptide but release of small transmitter and they require a really prolonged and rapid.
• Efficency is a action by Ca 2+ entering synapses (through NDMA).

Drugs that Target Chemical Synapses

• Affect NMDA with long term synaptic memories by change in growing of synaptic placticity. - Other molecules modifiy adenosine that affects synaptic activity on moment to moment basis.
• The small gases diffuse around brain.
• The connection from those neurons isn't transiting well but modulates well activity need for chains on change in allertness.
• Single exception bio act for protein channels with G-protien.