Motor end-plate – neuromuscular junction

Synaptic Communication

Pre-synaptic terminal

Post-synaptic terminal

Post-synaptic density

Vesicles

EPSP: Excitatory Post Synaptic Potential, fast or slow. The opening of sodium channels (tending to +50 mV) or opening of unselective channels (tending to -15 mV) would depolarize the cell.

IPSP: Inhibitory Post Synaptic Potential, fast or slow. The opening of potassium channels or chloride channels would hyperpolarize the cell. This would inhibit in another way as well: With greater overall permeability, the effectiveness of sodium channel openings would be reduced.

EPSP/IPSP

Temporal summation

Repeated firing of a presynaptic neuron produces repeated EPSPs in the same postsynaptic spine, giving summation in time but not over different places.

Spatial summationThe excitatory and inhibitory synapses are distributed in space, typically on widely spaced receptor clusters on dendrites, not (as shown here) so close on the cell soma. If depolarization (exitation +) exceeds hyperpolarization (inhibition -) by enough, the cell may fire.

Spatial versus temporal summation

Neurons can compute A neuron may receive 1,000 or more synaptic inputs but can only produce one kind of output, an action potential (or spike). For most neurons, the critical area for ‘deciding’ to fire a spike is the axon hillock, a region of the cell body at the beginning of the axon. The plasma membrane of the axon hillock is not insulated by myelin and has many voltage-gated ion channels.          Excitatory and inhibitory inputs from the synapses are conducted through the cell body by current flow. If the resulting combined potential depolarizes the axon hillock to threshold, the axon fires a spike. Synapses closer to the cell body generally have greater influence on the axon hillock because currents and potentials decrease as they spread passively (‘electrotonic conduction’) from the synapse.

(1) When the spike invades the synaptic terminal, (2) it opens voltage gated Ca2+ channels. (3) Entering Ca2+ triggers fusion of synaptic vesicles (exocytosis), each of which releases 100s or 1000s of neurotransmitter molecules into the synaptic cleft. (4) The transmitter diffuses across the cleft to bind to receptors on the post-synaptic membrane, causing (5) the dendrite to depolarize (EPSP) or hyperpolarize (IPSP). Transmitter may be cleared by re-uptake (6), diffusion (7), uptake by glia (8), and perhaps enzymatic degradation (9). Transmitter may activate autoreceptors (10) that reduce release rate.

Chemical synapse

Real appearance

Some synaptic transmitters

Different types of receptors

Ionotropic neurotransmitter receptors are ion channels.Metabotropic receptors are not themselves ion channels. Instead, they activate a “G protein”.

The G protein may open ion channels or may activate another protein (e.g., adenylyl cyclase) to generate another chemical (e.g., cAMP) that may affect ion channels, alter enzyme activity, or change gene expression. The transmitter is the ‘1st messenger’, whereas the internal chemical (e.g., cAMP) is the ‘2nd messenger’.

Cascade involving a 2nd messenger

Ligands

Ligands fit receptors and activate or block them:Endogenous ligands – neurotransmitters and hormonesExogenous ligands – drugs and toxins from outside the body

For example, a synapse that uses acetylcholine (ACh) has recognition sites for this endogenous ligand (ACh) within the receptor molecules in the postsynaptic membrane. ACh can be excitatory and open channels for Na+, or inhibitory and open channels for Cl- or K+.

An agonist

AntagonistA competitive antagonist binds the same site as the neurotransmitter.

A noncompetitive antagonist binds to a modulatory site.

Different pharmacologic types of acetylcholine receptor

Nicotinic (fast, ionotropic) cholinergic receptors are so named because they can be activated by nicotine (from tobacco), an agonist that mimics acetylcholine. These receptors are found on skeletal muscle at the neuromuscular junction, in autonomic ganglia, and in brain.

For this receptor, ligands like curare (from plants) and bungarotoxin (from snake venom) are antagonists (and thus paralytics).

Note five subunits ().

Different pharmacologic types of acetylcholine receptor

Muscarinic (slow, metabotropic) cholinergic receptors are so named because they can be activated by muscarine (from a poison mushroom), thus an agonist. Found on parasympathetic targets (smooth muscle, cardiac muscle) and in the brain, they can be excitatory or inhibitory.

Atropine (belladonna) and scopolamine are antagonists.

At first, the diversity of synaptic action was believed to be due to a diversity of neurotransmitters. In recent years, however, large numbers of different receptor subtypes for a given neurotransmitter have been discovered.

At first, pharmacological studies were the main technique used to subtype receptors.As noted, nicotinic acetylcholine receptors are "fast" and depolarize skeletal muscle. By contrast, muscarinic acetylcholine receptors are "slow" and (sometimes) hyperpolarize smooth muscle. (Both subtypes of receptors are found elsewhere in the nervous system, including the central nervous system.)

In recent years, cloning and sequencing of the genes for the subunits of receptors has shown an astonishing number and diversity of molecular subtypes of each pharmacological type of receptor.

A large number of different receptors

Ionotropic & metabotropic glutamate receptorsGlutamate is the main excitatory neurotransmitter in the brain. There are at least 4 pharmacologically defined glutamate receptor subtypes, AMPA, kainate and NMDA ionotropic ones and APB metabotropic ones. More than one type my reside in a single synapse!

Many receptor subtypes

In chemical synapses, the transmitter must be cleared rapidly from the synapse by

Clearance of transmitter

1. Diffusion (!)2. Re-uptake by the

presynaptic terminal, involving specific transporter proteins.

3. Uptake by glial cells, also involving transporters.

4. Enzymatic degradation e.g., acetylcholinesterase at the neuromuscular junction.

Eliminates 1 msec synaptic delay

Always sign preserving

Used in escape reflexes and situations requiring perfectsynchrony

Electrical synapses – gap

junctions

The sensory neuron (a muscle stretch receptor) synapses directly on the motor neuron in the spinal cord.

A simple neural chain: the knee jerk reflex

Neural chains are generally more complex

OptogeneticsOptogenetics uses genetic tools to insert light-sensitive ion channels

or pumps into neurons. Stimulating the brain with light, delivered by fiber-optic cables, can excite or inhibit those targeted neurons.

Some algae and bacteria produce light-sensitive proteins called opsins, which resemble the mammalian opsins found in light-receptor cells in our eye.

Channelrhodopsin responds to blue light by allowing Na+ ions to enter the genetically targeted cell, depolarizing it.

Halorhodopsin responds to yellow light by pumping Cl– ions into the cell, hyperpolarizing it.

Selective stimulation

By placing these proteins into specific cell types (e.g., GABAergic cells, synaptic targets of some pathway), it is possible to establish cause and effect for behavior.

Presynaptic drug mechanisms

local anesthetics

Postsynaptic drug mechanisms

(1) Physostigmine inhibits acetylcholinesterase, prolonging Ach action. (2) Ethanol increases number of GABA receptors. (3) Antipsychotic drugs block dopamine receptors. (4) Nicotine activates Ach receptors; LSD activates 5-HT receptors. (5) Lithium inhibits action of cAMP.

Binding affinity A given ligand, either the endogenous neurotransmitter or an exogenous drug, may bind with different affinities to different receptors. For any neurotransmitter, there are generally several pharmacological types of receptors and many molecular types for each pharmacological type. Binding affinity is the concentration of drug at which half the receptors are occupied by the drug, half are unoccupied.

Dose-response curves I: potency

ED50: Effective dose 50% Relative potency: A is more potent than B

Dose-response curves II: efficacy

Drug A has greater efficacy. Drug B may be termed a partial agonist (or partial antagonist).

LD50: Lethal dose 50%

Therapeutic index: Difference between LD50 and ED50. Drug A (blue) is safer than drug B (orange).