CELL-TO-CELL COMMUNICATION IN THE NERVOUS SYSTEM

1.            Synapses

a.            Synaptic transmission is the process by which nerve cells communicate among themselves and with muscles and glands through a minute space between them.

b.            Impulses are transmitted from one nerve cell to another cell at synapses.

c.         These are junctions where the axon or some other portion of one cell (the presynaptic cell) terminates on the dendrites, soma, or axon of another neuron or in some cases, a muscle or gland cell (the postsynaptic cell).

d.         Types of Synapse:

i.            axodendritic

ii.          axo-axonal

iii.            axosomatic

e.         The effects of discharge at individual synaptic endings can be excitatory or inhibitory.

f.          When the postsynaptic cell is a neuron, the summation of all the excitatory and inhibitory effects determines whether an action potential is generated.

g.         Thus, synaptic transmitssion is a complex process that permits the grading and adjustment of neural activity necessary for normal function.

2.            Electrical Synapses:

a.         pass an electrical signal or current directly away from the cytoplasm of one cell to another through gap junctions.

b.            synaptic transmission is accomplished by the passive electrotonic spread of current between two cells:

i.          when an action potential propagating along the membrane in one cell reaches the gap junction, an electrical current flows passively through the gap from one cell to another.

ii.            electrical current can pass through the gap in both directions, allowing either cell to serve as the pre- or postsynaptic cell.

c.         only 2nm separate the pre- and postsynaptic membranes at the site of gapjunctions.

d.         gap junctions are formed by membrane bridges that are constructed from integral membrane proteins called connexin.

e.         an aqueous channel is formed in the membrane by six connexin molecules

f.          found in:

i.          retina

ii.            olfactory bulb

g.            Importance:

i.          they play a vital role in coordinating muscle contraction in the heart and the viscera.

ii.          gap junctions rapidly transmit an action potential that is generated in one cell to all of the other cells within the organ, permitting the entire tissue to act as a syncytium and contract in a coordinated fashion.

3.         The vast majority of synapses in the nervous system are chemical synapses that use neurotransmitters to carry information from one cell to another.

4.            Neuromuscular Junction

a.         the site of communication between a alpha motor neuron and a skeletal muscle fiber.

b.         each synapse has three parts:

i.          the axon terminal of the presynaptic cell.

ii.          the synaptic cleft (30nm to 50nm) between the cells.

iii.         the membrane of the postsynaptic cell.

c.         The axon terminal of the nerve fiber branches at its end to form a complex of branching nerve terminals which are enlarged to form synaptic knobs (terminal buttons).

d.         the axon terminal lies in a groove called the synaptic trough, which is formed by an invagination of the skeletal muscle fiber.

e.         the synaptic knobs contains:

i.            synaptic vesicles (50nm in diameter) containing the neurotransmitter acetylcholine which are concentrated around specialized presynaptic membrane structures called dense bodies or active zones.

ii.            mitochondria which provide energy for the synthesis of acetylcholine.

iii.         rough ER for the transport of  CoA and choline, the precursors of acetylcholine as well as a store for vesicles.

f.          the synaptic cleft is filled with an amorphous network of connective tissue called basal lamina, in which the enzyme acetylcholinesterase is bound.

g.         the postsynaptic membrane contains:

i.            numerous junctional folds or subneural clefts, which are membrane invaginations located opposite the active zones; this increases the surface area on which the neurotransmitter can act on.

ii.            receptor sites for acetylcholine near the junctional folds.

h.            synaptic transmission occurs at the end-plate region (the postsynaptic membranes) of the skeletal muscle fiber.

5.            Convergence and Divergence

a.         only a few of the synaptic knobs on a postsynaptic neurons are endings of any single presynaptic neuron; the inputs to the cell are multiple.

b.         many presynaptic neurons converge on any single postsynaptic neuron.

c.         the axons of most presynaptic neurons divide into many branches that diverge to end on many postsynaptic neurons.

d.            convergence and divergence are the anatomic substrates for facilitation, occlusion and reverberation.

6.         One-way Conduction

a.            synapses generally permit conduction of impulses in one direction only (except in electrical synapses), from the presynaptic to the postsynaptic neurons.

b.            chemcial mediation at synaptic junctions explains one-way conduction:

i.          the mediator is located in the synaptic knobs of the presynaptic fibers but not in the postsynaptic membrane.

ii.            therefore an impulse arriving at the postsynaptic membrane cannot release synaptic mediator.

c.            progression of impulse traffic occurs only when the action potential arrives in the presynaptic terminals and causes secretion of stored chemical transmitter.

7.            Synthesis and recycling of acetylcholine at the synapse

a.            acetylcholine is made from choline and acetyl coenzyme A.

b.         choline is a small molecules also found in membrane phospholipids and acetyl CoA is the metabolic intermediates that links glycolysis to the citric acid cycle.

c.         small vesicles are formed by the Golgi apparatus in the cell body (soma) of the motor neuron in the spinal cord.

d.         these vesicles are then transported by the streaming of the axonplasm through the axon to the tips of the nerve fibers.

e.            acetylcholine is synthesized in the cytosol of the terminal nerve fibers, but is then transported through the membranes of the vesicles to their interior, where it is stored in highly concentrated forms, with about 10,000 molecules to each vesicles.

f.            spontaneous release of acetylcholine occurs by exocytosis:

i.          a vesicle binds to an attachment site on one of the active zones.

ii.          the vesicle fuses with the presynaptic membrane, extruding its contents to the synaptic cleft.

iii.            acetylcholine diffuses out of the vesicle into the synaptic cleft. and the vesicles merges with the presynaptic membrane.

g.         later, new vesicles are formed from the presynaptic membrane by endocytosis:

i.          the presynaptic membrane forms invaginations (caused by the contractile action of the protein clathrin beneath it) that eventually bud off to form new vesicles.

ii.          the new vesicles are refilled with acetylcholine again.

h.         the choline portion of the acetylcholine molecule is transported back into the axon terminal and is used to make more neurotransmitter.

8.         Events in synaptic transmission

a.         an action potential coming down the axon depolarizes the membrane of the axon terminal.

b.         the depolarization opens voltage-gated Ca²⁺ channels in the membrane so that Ca²⁺ enters the cell down its electrochemical gradient.

c.         the increase in intracellular Ca²⁺ concentration causes 200-300 vesicles to bind to attachment sites and release their contents into the synaptic cleft.

d.         the fusion of synaptic vesicles with the presynaptic terminal may be mediated by a protein called synapsin I:

i.          this protein inhibits exocytosis by tethering the vesicle to the cytoskeleton near active zones.

ii.          when Ca²⁺ enters the nerve terminal, it inititates phosphorylation of synapsin I via Ca²⁺ / calmodulin kinase II.

iii.         this loosens the association of the protein to the cytoskeleton.

iv.            phosphorylated synapsin I dissociates from the synaptic vesicle, allowing exocytosis to occur.

e.         the neurotransmitter released from the axon diffuses across the synaptic cleft and binds with receptors on the postsynaptic membrane.

f.          The acetylcholine receptor:

i.          they are nicotinic because they are stimulated by nicotine and inhibited by curare.

ii.          it is a transmembrane protein consisting of five subunits that form an aqueous channel within a lipid bilayer.

iii.         there are 2 alpha protein subunits and each of beta, delta and gamma proteins.

iv.         when 2 alpha subunits are occupied by acetylcholine, the proteins undergo a conformational change that opens a gate within the channel.

v.         hence, it is a chemically activated channel.

vi.         the open channel has a diameter of 0.65nm which allows Na⁺ and K⁺ ions to pass through but not Cl^- due to the strong negative charges at the mouth of the channel and hence it is a non-specific cation channel.

g.            depolarization:

i.          the influx of Na⁺ ions causes a depolarization of the postsynaptic membrane generating an end-plate potential (EPP).

ii.          the EPP is a graded response, not an all-or-none response: the magnitude of the depolarization is proportional to the number of open channels.

iii.         if a single vesicle releases its contents, the membrane will depolarize by 1mV; this is called a miniature end-plate potential (MEPP).

iv.         the MEPPs may be important in maintaining the integrity of the muscle fiber because denervation of skeletal muscle leads to muscle atrophy.

h.         the EPP initiates an action potential on the muscle fiber membrane:

i.          the EPP depolarizes the contiguous membrane regions to threshold, and an action potential is generated.

ii.          the action potential is propagated along the muscle membrane and is responsible for initiating a muscle contraction.

i.            acetycholine is degraded rapidly:

i.          after binding to the receptor, the acetylcholine dissociates from the receptor and is hydrolyzed by the acetylcholinesterase attached to the basal lamina in the synaptic cleft.

ii.            degradation of acetylcholine is necessary to prevent it from causing multiple muscle contractions.

iii.         some of the acetylcholine diffuses out of the synapse space and is lost.

iv.            enzymatic destruction is a unique method for inactivating the transmitter and occurs only at acetylcholine synapses.

9.         Action of the Transmitter Substance on the Postsynaptic Neuron

a.         the receptor proteins in the postsynaptic membrane is of two types:

i.          an ion channel that allows passage of specified types of ions through the channel.

ii.          a ‘second messenger’ activator that protrudes into the cell cytoplasm and activates one of more substances inside the postsynaptic neuron.

10.       The ion channels in the postsynaptic membrane is of two types:

a.         cation channels most often allow sodium ions to pass through but sometimes potassium or calcium ions.

b.         anion channels that allow mainly chloride ions to pass but also minute quantities of other anions.

c.         the cation channels that conduct sodium ions are lined with negative charges; these charges attract the positively charged sodium ions into the channel.

d.         for anion channels, they do not allow the passage of sodium, potassium and calcium ions which are hydrated.

e.         a transmitter substance that opens sodium channels is called an excitatory transmitter while those that opens chloride channels are inhibitory transmitters.

f.          when a transmitter substance activates an ion channel, the channel usually opens within a fraction of a millisecond; when the transmitter substance is no longer present, the channel closes equally rapidly.

g.            therefore, the opening and closing of ion channels provide a means for rapid activation or rapid inhibition of postsynaptic neurons.

11.       Second Messenger System in the Postsynaptic Neuron

a.         when a neurotransmitter binds to a receptor that is linked to a G protein-mediated second messenger system, the receptor diffuses within the membrane until it encounters a G protein complex.

b.         when the activated receptor binds to the G protein, it induces the G protein to exchange the GDP molecule that is bound to the alpha subunit for a GTP molecule.

c.         the presence of GTP causes the alpha subunit to separate from the G protein.

d.         the alpha subunit diffuses within the membrane until it encounters the enzyme that initiates the second messenger response.

e.         the G protein is inactivated  when GTP is converted to GDP.

f.          if the agonist binds to a muscarinic or alpha₁ receptor,

i.          the alpha subunit of the G protein activates phospholipase C, a membrane-bound lipase.

ii.          the phospholipase C, in turn, hydrolyzes phosphatidylinositol diphosphate (PIP₂) into inositol triphosphate (IP₃) and diacylglycerol (DAG)>

iii.         IP₃ enters the cytoplasm, where it liberates Ca²⁺ from internal stores.

iv.         the increase in intracellular Ca²⁺ leads to muscle contraction.

v.         DAG remains in the membrane and activates protein kinase C, a cytoplasmic enzyme that activates a series of cytoplasmic proteins by phosphorylating them.

g.         if the agonist binds to a beta receptor,

i.          the alpha subunit of the G protein activates adenylate cyclase.

ii.          the adenylate cyclase catalyzes the converstion of ATP to cAMP.

iii.         cAMP activates protein kinase A, which catalyzes the phosphorylation of cellular proteins.

12.       Other functions performed by the alpha subunit

a.         opening specific ion channels through the postsynaptic cell membrane which often stays open for a prolonged period of time.

b.            activation of one or more intracellular enzymes: the G-protein can directly activate one or more intracellular enzymes which in turn can cause any one of many specific chemical functions in the cell.

c.            activation of gene transcription can cause the formation of new proteins within the neuron and these can change the metabolic machinery of the cell or its structure.

13.       Fast and Slow responses

a.         in fast responses, the neurotransmitter opens a chemically gated ion channel, leading to ion movement between the cell and the extracellular fluid.

b.         the resulting change in membrane potential is a fast synaptic potential because it begins quickly and lasts only a few milliseconds.

c.         fast responses always open ion channels, but slow responses can close ion channels as well as open them.

d.         in slow responses, neurotransmitters bind to receptors linked to G proteins and second messenger systems.

e.         the second messengers act from the cytoplasmic side of the cell membrane to open or to close ion channels.

f.            membrane potentials resulting form this process are called slow synaptic potentials because the second messenger method takes longer to create a response.

g.         this type of slow response has been linked to the growth and development of neurons and to the mechanisms underlying long-term memory.

14.            Excitatory Postsynaptic Potentials (EPSP)

a.         ESPS are due to the depolarization of the membrane immediately under the synaptic knob producing small areas of current flow.

b.         the rapid influx of positively charged sodium ions to the interior increases the membrane potential and this increase in voltage is termed EPSP.

c.            because if the potential is high enough, it will elicit an action potential in the neuron, thus exciting it.

d.            discharge of a single presynaptic terminal can never increase the neuronal potential to the point of threshold.

e.         an increase of this magnitude depends on the simultaneous discharge of many terminals – a process called summation.

f.          the EPSP is therefore not an all or none response but is proportionate in size to the strength of the afferent stimulus; if the ESPS is large enough to reach the firing level of the cell, an action potential is produced.

g.         Ionic Basis of EPSPs:

i.            chemically gated ion channels are the basis for the generation of EPSPs.

ii.          the type of postsynaptic response depends on the type of channel it associates with.

iii.         an example is the production of EPSPs by acetylcholine at nicotinic synapses where acetylcholine is an excitatory transmitter.

iv.            acetylcholine binds to nicotinic receptors and this triggers the opening of channels that permit sodium ions tomove along its electrochemical gradient into the cell and an EPSP is produced.

v.            however the area in which this influx occurs is so small that repolarizing forces are able to overcome its influence and runaway depolarization of the whole membrane does not result.

vi.         if more excitatory synaptic knobs are active, more sodium ions enters and the depolarizing potential is greater.

vii.        if Na influx is great enough, the firing level is reached and a propagated action potential results.

viii.       EPSPs can also be produced by agents that close K channels.

15.            Inhibitory Postsynaptic Potential

a.         Causes:

i.          opening of chloride channels.

ii.          opening of potassium channels.

b.         the inhibitory synapses open mainly the chloride channels, allowing easy passage of chloride channels.

c.         opening the chloride channels will allow negatively charged chloride ions to move to the interior, which will make the membrane potential more negative than usual.

d.         opening potassium channels will allow positively charged potassium ions to move to the exterior, which will also make the membrane potential more negative than normal.

e.         this increases the degree of intracellular negativity, which is called hyperpolarization.

f.          it inhibits the neuron because the membrane potential is now further away than ever from the threshold for excitation.

g.         this type of inhibition is called postsynaptic or direct inhibition.

h.         neurons responsible for postsynaptic inhibition:

i.            stimulation of certain sensory nerve fibers known to pass directly to motor neurons in the spinal cord produces EPSPs in these neurons and IPSPs in other neurons.

ii.          in the inhibitory pathways, a single interneuron is inserted between the afferent dorsal root fiber and the motor neuron.

iii.         this special neuron is called a Golgi bottle neuron, is short and plump and has a thick axon.

iv.         its synaptic transmitter is glycine, and when this amino acid is secreted from its synaptic knobs to the proximal dendrites or cell body of the postsynaptic neuron, an IPSP is produced.

v.         this is due to an increase in the conductance of the postsynaptic cell membrane to chloride ions.

16.       Direct and Indirect Inhibition

a.            postsynaptic inhibition during the course of an IPSP is also called direct inhibition because it is not a consequence of previous discharges of the postsynaptic neuron.

b.         various forms of indirect inhibition due to the effects of previous postsynaptic neuron discharge also occur: the postsynaptic cell can be refractory to excitation because it has just fired and is in its refractory period.

17.            Postsynaptic Inhibition in the Spinal Cord

a.         afferent fibers from the muscle spindle in skeletal muscle pass directly to the spinal motor neurons of the motor units supplying the same muscle.

b.            impulses in this afferent supply cause EPSPs and, with summation, propagated responses in the postsynaptic motor neurons.

c.         at the same time the IPSPs are produced in motor neurons supplying the antagonistic muscles.

d.         this latter response is mediated by branches of the afferent fibers that end on Golgi bottle neurons.

e.         these neurons secrete glycine at synapses on the proximal dendrites or cell bodies of the motor neurons that supply the antagonist.

f.            therefore, activity in the afferent fibers from the muscle spindles excites the motor neurons supplying the muscle from which the impulses come and inhibits those supplying its antagonists (reciprocal innervation).

18.            Presynaptic Inhibition

a.         this type of inhibition occurs in the presynaptic terminals before the signal ever reaches the synapse.  

b.         in presynaptic inhibition, the inhibition is caused by discharge of inhibitory synapses that lie on the presynaptic terminal nerve fibrils, forming axo-axonal synapses before their endings terminate on the postsynaptic neuron.

c.            activation of the receptors mediating presynaptic inhibition reduces the amount of neurotransmitter secreted when action potentials arrive at excitatory synaptic knobs.

d.         this is achieved by:

i.            reducing the opening of Ca channels directly.

ii.            increases CI and/or K conductance.

e.         this makes the membrane more permeable, so that the size of the action potentials reaching the ending is reduced.

f.          in most instances, the inhibition transmitter released is GABA.

g.            presynaptic inhibition occurs in many of the sensory pathways in the nervous system: adjacent terminal nerve fibers mutually inhibit one another, which minimizes the sideways spread of signals in sensory tracts.

19.       ‘Short-Circuiting’ of the Membrane

a.            sometimes, activation of inhibitory synapses causes little or no IPSP but nevertheless inhibits the neuron.

b.         in some neurons, the concentration difference across the membrane for Cl^- ions cause a chloride Nernst potential that is exactly equal to its resting potential.

c.            therefore, when inhibitory channels open, there is no net flow of Cl^- ions to cause an inhibitory postsynaptic potential.

d.         yet the Cl^- ions do diffuse bidirectionally through the wide-open channels many times as rapidly as normally, and this high flux inhibits the neuron:

i.          when excitatory synapses cause Na⁺ ions to flow into the neuron, the wide-open Cl^- channels cause far less excitatory postsynaptic potential as usual.

ii.          the reason is that any change in the membrane potential now makes the potential different from the Cl^- Nernst potential.

iii.            therefore, net Cl^- ion flow through the membrane is no longer zero; instead extra Cl^- ions flow rapidly through the Cl^- channels and their electronegativity nullifies most of the electropositivity of the sodium-induced EPSP.

iv.         as a result, the amount of excitatory influx of Na⁺ ions needed to overcome the Cl^- flux to cause excitation is 5 to 20 times normal.

e.         this tendency for the Cl^-  ions to maintain membrane potential near the resting value when the inhibitory channels are wide open is called ‘short circuiting’ of the membrane.

20.            Presynaptic Facilitation is produced when the action potential is prolonged and the Ca channels are open for a longer period.

21.            Organization of Inhibitory Systems

a.            presynaptic and postsynaptic inhibition are usually produced by stimulation of certain systems converging on a given postsynaptic neuron.

b.         neurons may also inhibit themselves in a negative feedback fashion.

c.         spinal motor nerves regularly give off a recurrent collateral, which synapses with an inhibitory interneuron that terminates on the cell body of the spinal neuron and other spinal motor neurons.

d.         this particular inhibitory neuron is called the Renshaw cell.

e.            impulses generated in the motor neuron activate the inhibitory interneuron to secrete inhibitory mediator, and this slows or stops the discharge of the motor neuron.

f.          similar inhibition via recurrent collaterals is seen in the cerebral cortex and limbic system.

g.            presynaptic inhibition due to descending pathways that terminate on afferent pathways in the dorsal horn may be involved in the ‘gating’ of pain transmission.

h.         another type of inhibition is seen in the cerebellum:

i.            stimulation of basket cells produces IPSPs in the Purkinje cells.

ii.            however, the basket cells and the Purkinje cells are excited by the same excitatory input.

iii.         this arrangement, which is called ‘feed-forward inhibition’, limits the duration of the excitation produced by any given afferent impulse.