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]

Opioid receptor was present in the nerves associated with the portal vein that collects blood from the gut

  • Opioid Receptor Satiety Signal | Science Signaling

    The sensations of hunger and satiety are mediated through communication between the gastrointestinal system and the brain. Duraffourd et al. found that μ-opioid receptor (MOR)–1 was present in the nerves associated with the portal vein that collects blood from the gut. Peptide products of protein digestion can function …

    • stke.sciencemag.org/content/5/234/ec195

    DOI: 10.1126/scisignal.2003416

  • Synthesizing the Opioid Peptides

    Synthesizing the Opioid Peptides. The opioid peptides are synthesized as parts of large precursor molecules that may be split to yield different products in different cells. The biosynthesis of the opioid pep- tides illustrates what seemsto be a gen- eral trend in neurobiology. Likemany other peptides that act in the nervous.

    • science.sciencemag.org/content/sci/220/4595/395.full.pdf

    Drug, HIV crises hit HHS nominee Price close to home | Science …

    Dec 2, 2016  But Price’s district is also experiencing some public health crises that he will likely be dealing with as HHS secretary: a serious heroin and opioid abuse epidemic, as well as elevated HIV infection rates. The heroin problem was described in great detail in this investigative special by the local NBC affiliate …


    COMT val158met Genotype Affects µ-Opioid Neurotransmitter …

    We detected significant effects of genotype on μ-opioid system activation (degrees of freedom = 2, 15 for all regions,P < 0.05 after correction for multiple comparisons) in the anterior thalamus [x, y, zcoordinates (millimeters), 5, −1, −2; F = 29.3], the thalamic pulvinar ipsilateral to the painful challenge (x,y, z, −8, −24, 8; …

    • science.sciencemag.org/content/299/5610/1240.full

    DOI: 10.1126/science.1078546

  • Constitutive μ-Opioid Receptor Activity Leads to Long-Term …

    Pain and Dependence. The properties and functions of µ-opioid receptors have been studied intensively with respect to the binding of endogenous or exogenous ligands. However, much less is known about the constitutive, ligand-independent, activation of opioid receptors. Working in mice, Corder et al. (p. 1394) observed …

    • science.sciencemag.org/user/logout?current=node/494607
  • Even more pain in opioid treatment | Science

    Jul 8, 2016  Amid heightened concern about the addictive properties of opiates used to manage pain, new results from Grace et al. reveal that morphine can actually promote chronic pain. Rats with nerve damage treated for 5 days with morphine showed a sensitization to pain that persisted for months after opioid …

    • science.sciencemag.org/content/353/6295/134.3

    DOI: 10.1126/science.353.6295.134-c


    The opioid peptide dynorphin, circadian rhythms, and starvation …

    Abstract. Dynorphin, an opioid peptide whose functions are unknown, is found in brain, pituitary, and peripheral organs. Specific radioimmunoassays were used to measure dynorphin in the hypothalamus and pituitary, during the day and at night, as a function of food and water deprivation. Immunoreactive dynorphin was …

    • science.sciencemag.org/content/219/4580/71

    DOI: 10.1126/science.6129699


    Regulating Opioid Responses | Science Signaling

    Different drugs of abuse are thought to hijack similar reward systems in the brain using common mechanisms. However, Koo et al. now observe that some of the neural mechanisms that regulate opiate reward can be both different and even opposite to those that regulate reward by stimulant drugs. Whereas knockdown of …

    • stke.sciencemag.org/content/5/245/ec264?intcmp=trendmd-stke

    DOI: 10.1126/scisignal.2003665


    Opioid receptors undergo axonal flow | Science

    Abstract. Previous studies have indicated the presence of opiate receptors on axons of the rat vagus nerve and on other small diameter fibers. In examinations of the effect of ligation on the distribution of receptors in the vagus nerve by in vitro labeling light microscopic autoradiography, a large buildup of receptors was found …

    • science.sciencemag.org/content/210/4465/76

    DOI: 10.1126/science.6158097


    Opioid peptides may excite hippocampal pyramidal neurons by …

    Abstract. The atypical excitation by opiates and opioid peptides of hippocampal pyramidal cells can be antagonized by iontophoresis of naloxone, the gamma-aminobutyric acid antagonists bicuculline, or magnesium ion. The recurrent inhibition of these cells evoked by transcallosal stimulation of the contralateral …

    • science.sciencemag.org/content/205/4404/415

    DOI: 10.1126/science.451610

Oxytocin Helps the Brain Modulate Social Signals

Oxytocin Helps the Brain Modulate Social Signals

Summary: A new study reports oxytocin plays a crucial role in processing numerous social signals.

Source: Harvard.

Between sights, sounds, smells and other senses, the brain is flooded with stimuli on a moment-to-moment basis. How can it sort through the flood of information to decide what is important and what can be relegated to the background?

Part of the answer, says Catherine Dulac, the Higgins Professor of Molecular and Cellular Biology, may lie with oxytocin.

Though popularly known as the “love hormone,” Dulac and a team of researchers found evidence that oxytocin actually plays a crucial role in helping the brain process a wide array of social signals. The study is described in a December 12 paper published in eLife.

The study, Dulac said, suggests that oxytocin acts like a modulator in the brain, turning up the volume of certain stimuli while turning others down, helping the brain to make sense of the barrage for information it receives from one moment to the next.

In investigating the role of oxytocin in processing social signals, Dulac and colleagues began with an oft-observed behavior – the preference for male mice to interact with females.

Studies have shown that this behavior isn’t just social – it’s actually hard-wired in the brains of male mice.

When male mice are exposed to pheromone signals of females, Dulac and colleagues found, neurons in their medial amygdala showed increased levels of activation. When the same mice were exposed to pheromones of other males, those same neurons showed relatively little stimulation.

Armed with that data, Dulac and colleagues targeted the gene responsible for producing oxytocin – which was known to be involved in social interactions ranging from infant/parent bonding to monogamy in certain rodents.

Using genetic tools, researchers switched the gene off, and were surprised to find that both males’ preference for interacting with females and the neural signal in the amygdala disappeared.

“This is a molecule that’s involved in the processing of social signals,” Dulac said. “We also showed, using pharmacology and genetics, that the effect happens on a moment-to-moment basis.

“What we are trying to do is understand the logic of social interactions in one particular species,” she said. “What this study says is, for this particular type of social interaction, oxytocin plays a role, and that role is both at the level of the brain and the behavior.”


Understanding oxytocin – and molecules like it – might shed light on a number of brain disorders.

With an understanding of how various neurotransmitters work to amplify or quiet certain stimuli, Dulac said, researchers may gain new insight into how to treat everything from depression, which is often characterized by a lack of interest in social interactions, to autism, which is thought to be connected to an inability to sort through social and sensory stimuli.

Ultimately, Dulac said, the study offers a small glimpse into what could be a larger system of molecules which act like modulators in the brain, turning certain stimuli up or down depending on the situation.

“There may be many different regulators,” Dulac said. “Oxytocin might be one of a whole realm of modulators, each of which are important in a particular circumstance. That therefore gives the animal a great deal of plasticity in terms of engaging in a particular behavior, so it’s not the case that each time the animal encounters a particular stimulus it will react in exactly the same way. Depending on the state of the brain and the release of these neurotransmitters, the animal can boost its behavior toward the stimulus or ignore it.”


Source: Harvard
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Dulac et al./eLife.
Original Research: Full open access research for “Oxytocin signaling in the medial amygdala is required for sex discrimination of social cues” by Shenqin Yao, Joseph Bergan, Anne Lanjuin, and Catherine Dulac in eLife. Published online December 12 2017 doi:10.7554/eLife.31373

Harvard “Oxytocin Helps the Brain Modulate Social Signals.” NeuroscienceNews. NeuroscienceNews, 17 January 2018.


Oxytocin signaling in the medial amygdala is required for sex discrimination of social cues

The neural control of social behaviors in rodents requires the encoding of pheromonal cues by the vomeronasal system. Here we show that the typical preference of male mice for females is eliminated in mutants lacking oxytocin, a neuropeptide modulating social behaviors in many species. Ablation of the oxytocin receptor in aromatase-expressing neurons of the medial amygdala (MeA) fully recapitulates the elimination of female preference in males. Further, single-unit recording in the MeA uncovered significant changes in the sensory representation of conspecific cues in the absence of oxytocin signaling. Finally, acute manipulation of oxytocin signaling in adults is sufficient to alter social interaction preferences in males as well as responses of MeA neurons to chemosensory cues. These results uncover the critical role of oxytocin signaling in a molecularly defined neuronal population in order to modulate the behavioral and physiological responses of male mice to females on a moment-to-moment basis.

“Oxytocin signaling in the medial amygdala is required for sex discrimination of social cues” by Shenqin Yao, Joseph Bergan, Anne Lanjuin, and Catherine Dulac in eLife. Published online December 12 2017 doi:10.7554/eLife.31373