Silent synapse
Encyclopedia
In neuroscience
, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane
contains NMDA-type glutamate receptors
but no AMPA-type glutamate receptors
. These synapse
s are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be made silent by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.
Normal transmission across an excitatory synapse relies on the neurotransmitter
glutamate, the glutamate-specific AMPA receptor
(AMPAR), and calcium
ion
s. Calcium ion entry into the presynaptic terminal causes the presynaptic release of glutamate which diffuses across the synaptic cleft binding to glutamate receptors on the postsynaptic membrane. There are four main types of glutamate receptors: AMPA receptors (AMPARs), NMDA receptors (NMDARs), Kainate receptors, and quisqualate receptors, some of which are also metabotropic receptor
s. Most research has been focused on the AMPARs and the NMDARs. When glutamate binds to AMPARs located on the postsynaptic membrane, they permit a mixed flow of Na+ and K+ to cross the cells membrane, causing a depolarization of the postsynaptic membrane. This depolarization is called the excitatory postsynaptic potential
(EPSP).
Silent synapses release glutamate as do "normal" synapses, but they lack AMPARs on the surface membrane of the postsynapse. Only NMDARs (and perhaps metabotropic receptors) are found in the surface postsynaptic membrane where they can bind synaptically released glutamate. AMPARs are not completely absent from silent synapses, they are simply located inside the postsynaptic cell, where they cannot detect extracellular glutamate. The NMDAR is functionally similar to AMPAR except for two major differences: NMDARs carry ion currents composed of Na+, K+, but also (unlike most AMPAR) Ca2+; NMDARs also have a site inside their ion channel that binds magnesium ions (Mg2+). This magnesium binding site is physically located in the channel at a place within the electrical field generated by the membrane potential. Normally, current will not flow though the NMDAR channel, even when it has bound glutamate. This is because the ion channel associated with this receptor is plugged by magnesium, acting like a cork in a bottle. However, since the Mg2+ is charged and is bound within the membrane's electric field, depolarization of the membrane potential above threshold can dislodge the magnesium, allowing current flow through the NMDAR channel. This gives the NMDAR the property of being voltage-dependent, in that it requires strong postsynaptic depolarization
to allow ion flux.
at -60 mV
. Stimulation of a silent synapse will elicit EPSPs when the postsynaptic cell is depolarized beyond -40 mV. This is because they lack surface AMPAR to pass current at hyperpolarized potentials, but do possess NMDARs that will pass current at more positive potentials (because of relief of magnesium block) Moreover, the EPSPs elicited with depolarized membrane potentials can be completely blocked by APV
, a selective NMDAR blocker.
When glutamate binds to a strongly-depolarized postsynaptic cell (e.g., during Hebbian LTP), Ca2+ quickly enters and binds to calmodulin
. Calmodulin activates calcium/calmodulin-dependent protein kinase II (CaMKII), which — among other things — acts on AMPAR-containing vesicle
s near the postsynaptic membrane. CaMKII phosphorylates
these AMPARs, which serves as a signal to insert them into the postsynaptic membrane. Once AMPARs are inserted, the synapse is no longer silent; activated synapses no longer require simultaneous pre- and postsynaptic activity in order to elicit EPSPs.
Evidence suggests that dendrite arborization and synapse maturation 1 (Dasm1),an Ig superfamily member, is involved in the maturation of synapses, essentially "awakening" the silent synapses.
All four of these hypotheses had their adherents, but the first three were largely ruled out as a mechanism for synapse silence by work published since 2002 (e.g. Montgomery et al. 2002). However, recent experiments (Balland et al. 2008) have clearly established that silent synapses can be observed at brainstem synapses bearing postsynaptic AMPA receptors. This study favors the glutamate spillover hypothesis by showing that at silent synapses the glutamate concentration is reduced. At least, this study indicates that the popular hypothesis of the postsynaptic silent synapses does not apply in all systems.
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...
, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
contains NMDA-type glutamate receptors
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
but no AMPA-type glutamate receptors
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
. These synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be made silent by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.
Synaptic transmission
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
glutamate, the glutamate-specific AMPA receptor
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
(AMPAR), and calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s. Calcium ion entry into the presynaptic terminal causes the presynaptic release of glutamate which diffuses across the synaptic cleft binding to glutamate receptors on the postsynaptic membrane. There are four main types of glutamate receptors: AMPA receptors (AMPARs), NMDA receptors (NMDARs), Kainate receptors, and quisqualate receptors, some of which are also metabotropic receptor
Metabotropic receptor
Metabotropic receptor is a subtype of membrane receptors at the surface or in vesicles of eukaryotic cells.In the nervous system, based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors...
s. Most research has been focused on the AMPARs and the NMDARs. When glutamate binds to AMPARs located on the postsynaptic membrane, they permit a mixed flow of Na+ and K+ to cross the cells membrane, causing a depolarization of the postsynaptic membrane. This depolarization is called the excitatory postsynaptic potential
Excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels...
(EPSP).
Silent synapses release glutamate as do "normal" synapses, but they lack AMPARs on the surface membrane of the postsynapse. Only NMDARs (and perhaps metabotropic receptors) are found in the surface postsynaptic membrane where they can bind synaptically released glutamate. AMPARs are not completely absent from silent synapses, they are simply located inside the postsynaptic cell, where they cannot detect extracellular glutamate. The NMDAR is functionally similar to AMPAR except for two major differences: NMDARs carry ion currents composed of Na+, K+, but also (unlike most AMPAR) Ca2+; NMDARs also have a site inside their ion channel that binds magnesium ions (Mg2+). This magnesium binding site is physically located in the channel at a place within the electrical field generated by the membrane potential. Normally, current will not flow though the NMDAR channel, even when it has bound glutamate. This is because the ion channel associated with this receptor is plugged by magnesium, acting like a cork in a bottle. However, since the Mg2+ is charged and is bound within the membrane's electric field, depolarization of the membrane potential above threshold can dislodge the magnesium, allowing current flow through the NMDAR channel. This gives the NMDAR the property of being voltage-dependent, in that it requires strong postsynaptic depolarization
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
to allow ion flux.
Characteristics
The stimulation of a silent synapse does not elicit EPSPs when the postsynaptic cell is clampedVoltage clamp
The voltage clamp is used by electrophysiologists to measure the ion currents across the membrane of excitable cells, such as neurons, while holding the membrane voltage at a set level. Cell membranes of excitable cells contain many different kinds of ion channels, some of which are voltage gated...
at -60 mV
Volt
The volt is the SI derived unit for electric potential, electric potential difference, and electromotive force. The volt is named in honor of the Italian physicist Alessandro Volta , who invented the voltaic pile, possibly the first chemical battery.- Definition :A single volt is defined as the...
. Stimulation of a silent synapse will elicit EPSPs when the postsynaptic cell is depolarized beyond -40 mV. This is because they lack surface AMPAR to pass current at hyperpolarized potentials, but do possess NMDARs that will pass current at more positive potentials (because of relief of magnesium block) Moreover, the EPSPs elicited with depolarized membrane potentials can be completely blocked by APV
APV (NMDAR antagonist)
AP5 or APV is a selective NMDA receptor antagonist that competitively inhibits the ligand binding site of NMDA receptors....
, a selective NMDAR blocker.
Activation
Silent synapses are activated via the insertion of AMPARs into the postsynaptic membrane, a phenomenon commonly called "AMPA receptor trafficking".When glutamate binds to a strongly-depolarized postsynaptic cell (e.g., during Hebbian LTP), Ca2+ quickly enters and binds to calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
. Calmodulin activates calcium/calmodulin-dependent protein kinase II (CaMKII), which — among other things — acts on AMPAR-containing vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
s near the postsynaptic membrane. CaMKII phosphorylates
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
these AMPARs, which serves as a signal to insert them into the postsynaptic membrane. Once AMPARs are inserted, the synapse is no longer silent; activated synapses no longer require simultaneous pre- and postsynaptic activity in order to elicit EPSPs.
Evidence suggests that dendrite arborization and synapse maturation 1 (Dasm1),an Ig superfamily member, is involved in the maturation of synapses, essentially "awakening" the silent synapses.
Controversy
The characterization of silent synapses is an ongoing field of research and there are many things about them that are not yet known. Some of what is currently accepted about the properties of silent synapses may still prove to be incorrect in whole or in part. Some controversies about silent synapses have however, been settled. For example, until recently, there were four competing hypotheses for the mechanisms of synapse silence (see Voronin et al., 2004).- The whispering synapse hypothesis
- a synapse that releases glutamate more slowly than normal, thus activating only high affinity NMDA receptors, but not low affinity AMPA receptors
- The low Pr synapse hypothesis
- a synapse that is not technically silent, but appears to be so, because it has such a low presynaptic probability of release that it rarely is activated.
- The glutamate spillover hypothesis
- a synapse that does not release its own presynaptic glutamate, but in which the postsynapse detects low concentrations of glutamate "spilling over" from neighboring synapses. Only the high affinity NMDARs, but not the low affinity AMPARs can detect this low level of glutamate
- The lack of AMPA receptor hypothesis
- a synapse that lacks postsynaptic AMPA receptors
All four of these hypotheses had their adherents, but the first three were largely ruled out as a mechanism for synapse silence by work published since 2002 (e.g. Montgomery et al. 2002). However, recent experiments (Balland et al. 2008) have clearly established that silent synapses can be observed at brainstem synapses bearing postsynaptic AMPA receptors. This study favors the glutamate spillover hypothesis by showing that at silent synapses the glutamate concentration is reduced. At least, this study indicates that the popular hypothesis of the postsynaptic silent synapses does not apply in all systems.