Early synapse loss to Alzheimer’s disease

synapse loss.JPG


Structure of a typical chemical synapse

In the nervous system, a synapse[1] is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target efferent cell.

Santiago Ramón y Cajal proposed that neurons are not continuous throughout the body, yet still communicate with each other, an idea known as the neuron doctrine.[2] The word “synapse” – from the Greek synapsis (συνάψις), meaning “conjunction”, in turn from συνάπτεὶν (συν (“together”) and ἅπτειν (“to fasten”)) – was introduced in 1897 by the English neurophysiologist Charles Sherringtonin Michael Foster‘s Textbook of Physiology.[1] Sherrington struggled to find a good term that emphasized a union between two separate elements, and the actual term “synapse” was suggested by the English classical scholar Arthur Woollgar Verrall, a friend of Michael Foster.[3][4]Some authors generalize the concept of the synapse to include the communication from a neuron to any other cell type,[5] such as to a motor cell, although such non-neuronal contacts may be referred to as junctions (a historically older term).

Synapses are essential to neuronal function: neurons are cells that are specialized to pass signals to individual target cells, and synapses are the means by which they do so. At a synapse, the plasma membrane of the signal-passing neuron (the presynaptic neuron) comes into close apposition with the membrane of the target (postsynaptic) cell. Both the presynaptic and postsynaptic sites contain extensive arrays of a molecular machinery that link the two membranes together and carry out the signaling process. In many synapses, the presynaptic part is located on an axon and the postsynaptic part is located on a dendrite or somaAstrocytes also exchange information with the synaptic neurons, responding to synaptic activity and, in turn, regulating neurotransmission.[6] Synapses (at least chemical synapses) are stabilized in position by synaptic adhesion molecules (SAMs) projecting from both the pre- and post-synaptic neuron and sticking together where they overlap; SAMs may also assist in the generation and functioning of synapses.[7]

Chemical or electrical

An example of chemical synapse by the release of neurotransmitters like acetylcholine or glutamic acid.

There are two fundamentally different types of synapses:

  • In a chemical synapse, electrical activity in the presynaptic neuron is converted (via the activation of voltage-gated calcium channels) into the release of a chemical called a neurotransmitter that binds to receptors located in the plasma membrane of the postsynaptic cell. The neurotransmitter may initiate an electrical response or a secondary messenger pathway that may either excite or inhibit the postsynaptic neuron. Chemical synapses can be classified according to the neurotransmitter released: glutamatergic (often excitatory), GABAergic (often inhibitory), cholinergic (e.g. vertebrate neuromuscular junction), and adrenergic (releasing norepinephrine). Because of the complexity of receptor signal transduction, chemical synapses can have complex effects on the postsynaptic cell.
  • In an electrical synapse, the presynaptic and postsynaptic cell membranes are connected by special channels called gap junctions or synaptic cleft that are capable of passing an electric current, causing voltage changes in the presynaptic cell to induce voltage changes in the postsynaptic cell. The main advantage of an electrical synapse is the rapid transfer of signals from one cell to the next.[8]

Synaptic communication is distinct from an ephaptic coupling, in which communication between neurons occurs via indirect electric fields.

An autapse is a chemical or electrical synapse that forms when the axon of one neuron synapses onto dendrites of the same neuron.

Types of interfaces

Synapses can be classified by the type of cellular structures serving as the pre- and post-synaptic components. The vast majority of synapses in the mammalian nervous system are classical axo-dendritic synapses (axon synapsing upon a dendrite), however, a variety of other arrangements exist. These include but are not limited to axo-axonic, dendro-dendritic, axo-secretory, somato-dendritic, dendro-somatic, and somato-somatic synapses.

The axon can synapse onto a dendrite, onto a cell body, or onto another axon or axon terminal, as well as into the bloodstream or diffusely into the adjacent nervous tissue.

Different types of synapses

Role in memory

It is widely accepted that the synapse plays a role in the formation of memory. As neurotransmitters activate receptors across the synaptic cleft, the connection between the two neurons is strengthened when both neurons are active at the same time, as a result of the receptor’s signaling mechanisms. The strength of two connected neural pathways is thought to result in the storage of information, resulting in memory. This process of synaptic strengthening is known as long-term potentiation.[9]

By altering the release of neurotransmitters, the plasticity of synapses can be controlled in the presynaptic cell. The postsynaptic cell can be regulated by altering the function and number of its receptors. Changes in postsynaptic signaling are most commonly associated with a N-methyl-d-aspartic acid receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) due to the influx of calcium into the post-synaptic cell, which are the most analyzed forms of plasticity at excitatory synapses.[10]

Study models

For technical reasons, synaptic structure and function have been historically studied at unusually large model synapses, for example:

Synaptic polarization

The function of neurons depends upon cell polarity. The distinctive structure of nerve cells allows action potentials to travel directionally (from dendrites to cell body down the axon), and for these signals to then be received and carried on by post-synaptic neurons or received by effector cells. Nerve cells have long been used as models for cellular polarization, and of particular interest are the mechanisms underlying the polarized localization of synaptic molecules. PIP2 signaling regulated by IMPase plays an integral role in synaptic polarity.

Phosphoinositides (PIP, PIP2, and PIP3) are molecules that have been shown to affect neuronal polarity.[12] A gene (ttx-7) was identified in Caenorhabditis elegans that encodes myo-inositol monophosphatase (IMPase), an enzyme that produces inositol by dephosphorylating inositol phosphate. Organisms with mutant ttx-7 genes demonstrated behavioral and localization defects, which were rescued by expression of IMPase. This led to the conclusion that IMPase is required for the correct localization of synaptic protein components.[13][14] The egl-8 gene encodes a homolog of phospholipase Cβ (PLCβ), an enzyme that cleaves PIP2. When ttx-7 mutants also had a mutant egl-8 gene, the defects caused by the faulty ttx-7 gene were largely reversed. These results suggest that PIP2 signaling establishes polarized localization of synaptic components in living neurons.[13]

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Use It or Lose It

Use It or Lose It

Summary: LMU researchers report neural activity in the auditory system has a direct effect on myelination. Higher levels of neural activity resulted in the formation of thicker myelin sheaths and enhanced speed of signal transmission.

Source: LMU.

An LMU study reveals that sound-evoked activity of neurons in the auditory system of the mouse increases the thickness of their myelin sheaths – and enhances the speed of signal transmission – both during development and in the adult brain.

Nerve cells communicate by means of electrical impulses, which are transmitted along neural processes known as axons.

The speed of transmission depends on several factors, including the diameter of the axon and the thickness of the electrically insulating myelin sheaths that surround the axons.

As a rule, transmission speeds are positively correlated with the diameter and the thickness of the sheath. In mammals, the functional demands made on the auditory system require extremely precise and rapid neural processing of acoustic information, and it contains a strikingly high proportion of myelinated axons.

Using the mouse as an experimental model, LMU neurobiologist PD Dr. Conny Kopp-Scheinpflug and her research group have now demonstrated that the activity of nerve cells in the auditory system has a direct effect on myelinization – higher levels of activity correlate with the formation of thicker myelin sheaths. Their findings appear in the Journal of Neuroscience.

Specialized sensory neurons in the inner ear, called hair cells, are responsible for the detection of sounds, and this information is transmitted to the auditory cortex via several intermediate structures.

“The mouse is a particularly suitable model in which to study the development of the auditory system, because newborn mice are deaf and only begin to perceive acoustic signals at 12 days after birth. At this point, the level of activity of auditory neurons begins to increase,” Kopp-Scheinpflug explains.

She and her colleagues focused on the neuronal activity in the trapezoid body, a structure located in the brainstem that forms part of the pathway that eventually leads to the auditory cortex.

They were able to demonstrate that both the speed and frequency of signal transmission in the trapezoid body doubles as soon as the young mice begin to perceive sounds. Moreover, both the diameter of the axons and the thickness of their myelin sheaths progressively increased until they reached the values observed in the auditory system of the adult animal.

In addition, the team explored the developmental impact of reduced stimulation on the axons in the trapezoid body.

“To do so, we simply inserted earplugs in the ears of 10-day-old mice and left them in position for 10 more days. This intervention leads to a reversible hearing loss, i.e. rise in the hearing threshold of about 50 decibels“, says Kopp-Scheinpflug.

In these animals, the normal increase in axon diameter is mostly absent, and the myelin sheaths are also thinner. When the same experiment was carried out on adult mice, a decrease in the thickness of the myelin sheaths was also seen, although the diameter of the axons was not affected. Based on these results, the researchers conclude that neuronal activity itself plays an important role in the synthesis and maintenance of the myelin sheath, and that myelinated nerve cells therefore require a minimal level of sound-evoked stimulation.

Image shows neurons.

“In order to understand the effects of reduced stimulation, we also developed a computer model based on our results. The model predicts that not only axonal conductivity, but also the capacity to transmit high-frequency action potentials should decline,” says Kopp-Scheinpflug.

“Such losses are particularly critical in the auditory system, because they reduce the temporal precision of signal transmission – and the quality of our perception of the acoustic environment is primarily dependent on rates of action potential generation and precise neural computation of their temporal sequences.”


Source: Luise Dirscherl – LMU
Image Source: NeuroscienceNews.com image is credited to J. Sinclair & C. Kopp-Scheinpflug, LMU.
Original Research: Abstract for “Sound-evoked activity influences myelination of brainstem axons in the trapezoid body” by James L. Sinclair, Matthew J. Fischl, Olga Alexandrova, Martin Heß, Benedikt Grothe, Christian Leibold and Conny Kopp-Scheinpflug in Journal of Neuroscience. Published online July 31 2017 doi:10.1523/JNEUROSCI.3728-16.2017

LMU “Use It or Lose It.” NeuroscienceNews. NeuroscienceNews, 2 August 2017.


Sound-evoked activity influences myelination of brainstem axons in the trapezoid body

Plasticity of myelination represents a mechanism to tune the flow of information by balancing functional requirements with metabolic and spatial constraints. The auditory system is heavily myelinated and operates at the upper limits of action potential generation frequency and speed observed in the mammalian CNS.

This study aimed to characterize the development of myelin within the trapezoid body, a central auditory fiber tract, and determine the influence sensory experience has on this process in mice of both sexes.

We find that in vitro conduction speed doubles following hearing onset and the ability to support high frequency firing increases concurrently. Also in this time, the diameter of trapezoid body axons and the thickness of myelin double, reaching mature-like thickness between 25-35 days of age. Earplugs were used to induce approximately 50dB elevation in auditory thresholds.

If introduced at hearing onset, trapezoid body fibers developed thinner axons and myelin than age-matched controls.

If plugged during adulthood, the thickest trapezoid body fibers also showed a decrease in myelin.

These data demonstrate the need for sensory activity in both development and maintenance of myelin and have important implications in the study of myelin plasticity and how this could relate to sensorineural hearing loss following peripheral impairment.


The auditory system has many mechanisms to maximize the dynamic range of its afferent fibers, which operate at the physiological limit of action potential generation, precision and speed.

In this study we demonstrate for the first time that changes in peripheral activity modifies the thickness of myelin in sensory neurons, not only in development but also in mature animals.

The current study suggests that changes in CNS myelination occur as a downstream mechanism following peripheral deficit.

Given the required submillisecond temporal precision for binaural auditory processing, reduced myelination might augment sensorineural hearing impairment.

“Sound-evoked activity influences myelination of brainstem axons in the trapezoid body” by James L. Sinclair, Matthew J. Fischl, Olga Alexandrova, Martin Heß, Benedikt Grothe, Christian Leibold and Conny Kopp-Scheinpflug in Journal of Neuroscience. Published online July 31 2017 doi:10.1523/JNEUROSCI.3728-16.2017

The Aging but Resilient Brain: Keeping Neurons Happy

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What-makes-the-brain-works-and-why-it ages and becomes unhealthy [PPT]