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]

UC biologists find link between paternal diet and offspring’s health

UC biologists find link between paternal diet and offspring’s health

Doctors long have stressed the importance of good nutrition for expectant mothers.

Now biologists at the University of Cincinnati say the father’s diet could play a similar role in the health of a baby.

UC biology professors Michal Polak and Joshua Benoit manipulated the nutrition of male fruit flies and observed a strong correlation between poor diet and poor survivorship among their offspring. The study was published this week in the journal Proceedings of the Royal Society B.

“We were really surprised,” Polak said. “In many species, the moms do a lot of the care. So we expect there to be an effect from maternal diet on offspring because of that strong link. But it was a real surprise to find a link between paternal diet and offspring.”

UC collaborated on the study with researchers from the University of Western Australia and the University of Sydney’s Charles Perkins Centre.

Everyone knows a father is responsible for half of his offspring’s genes. But the UC study comes at a time when researchers are learning more about other influences fathers have on their offspring’s health that are not necessarily coded within genes, a concept called epigenetics. These influences include direct environmental effects such as exposure to toxins that can be passed from the father to his offspring through his seminal plasma.

Epigenetics is the way by which cells read genes, making some dormant and others active. Environmental cues can turn certain genes on or off. And these epigenetic modifications, too, can be inherited.

For example, an Australian study in 2016 found that male mice that lived on the equivalent of a fast-food diet were more likely to have sons that were diabetic even though daughters remained unaffected. If these traits were coded in the father’s DNA, both sons and daughters would see similar health effects.

“Epigenetic changes are seen in population genetics as less durable than actual mutations to the genetic code or DNA molecule,” Polak said. “If it’s a dominant, deleterious mutation, it could be quickly eliminated out of a gene pool by selection. But if it’s positively selected, then it could sweep the gene pool and increase in frequency until it becomes fixed.”

Research on fruit flies has earned six Nobel Prizes, including this year’s winner in physiology or medicine. The latest Nobel Prize study examined how genes control body clocks or circadian rhythms, which can help explain why some people have chronic trouble sleeping.

“I am very pleased for the field. I am very pleased for the fruit fly,” co-winner Michael Rosbash told The Associated Press.

Fruit flies are found around the world. UC’s Benoit even saw them buzzing around inside a research station in Antarctica, where they probably stowed away on food supplies imported from Chile.

The flies became popular study subjects in the early 1900s when biologists began to unravel how genetic inheritance worked. High school biology textbooks still use the color of fruit fly eyes to illustrate the concept.

Today, scientists regularly study fruit flies because they share 60 percent of our genes and more than 75 percent of our disease genes. Geneticists have mapped their entire genome. More than 150 years of study have made this unassuming little fly a good model system, Polak said.

“It’s almost arbitrary why fruit flies were chosen,” Polak said. “It just became the workhorse in those original labs.”

Benoit said flies are a practical and inexpensive test subject.

“They reproduce quickly. You can rear a few hundred in just one of these little jars. You can have thousands of fruit flies in the same amount of space you could fit six mice,” Benoit said. “It’s a great system to work on. That’s why so many questions have been answered about them.”

For the UC study, Polak isolated females and males of the fruit fly species Drosophila melanogaster, which is famous for its enormous red eyes and high reproductive capacity. A single fly can lay 50 eggs per day or as many as 2,000 eggs in her short two-month lifetime.

UC researchers fed females the same diet. But they fed males 30 different diets of yeast and sugars. The flies could eat all they wanted from the agar mixture in the bottom of their glass beaker homes, but the quality of the food varied dramatically from low to high concentrations of proteins, carbohydrates and calories.


After 17 days on the strict diet, the males were mated individually and consecutively with two females, which all received the same diet of yeasted cornmeal. By controlling the diet and age of the mated female, researchers tried to limit variation in maternal conditions for the study.

And by mating the males consecutively, researchers wanted to learn about the effect of male mating order and what role diet played in changing the male’s ejaculate.

After the first mating, the male fly was mated 15 minutes later with a second female. Afterward, the females were placed in isolated breeding vials filled with grape agar suitable for laying eggs. After 24 hours, researchers counted their eggs.

After another 24-hour incubation period, the eggs were examined under a microscope to determine how many hatched or contained viable embryos. Unfertilized eggs were removed from consideration. After the first count, researchers waited another 24 hours to give potentially unviable eggs time to develop or hatch but none did.

Polak and Benoit found that embryos from the second mating were more likely to survive as their fathers’ diets improved in nutrition. These effects were less apparent in the first mating. Likewise, embryo mortality was highest for offspring of males that fed on a high-carbohydrate, low-protein diet.

Researchers also found a connection between the male’s body condition and his offspring’s mortality. Males with lower energy reserves (measured in whole-body fatty acids, glucose and protein) were more likely to have fewer surviving offspring.

Females laid roughly the same number of eggs regardless of the male’s diet or mating frequency. But the study suggested that something important in the male’s ejaculate was lost between the first and second pairings.

“The second copulation is where the effects of diet really became stronger,” Polak said. “Emaciated males in poor condition produced embryos with a higher rate of mortality. But only in the second copulation.”

Polak’s study also found a slightly higher incidence of embryo mortality associated with male flies in the first mating that were fed the highest-calorie diet.

“There have been a fair number of studies that suggest male nutrition does affect reproductive capacity,” Benoit said. “But the reduction in viability was a lot smaller than what we saw in the low-quality diet or may have been masked since only a single mating was assessed.”

Polak said the study raises questions about how nutrition might affect successive generations. A 2002 Swedish population study found a correlation between 9-year-old children who had ample access to food and higher rates of diabetes and heart disease among their grandchildren. Meanwhile, children who faced privation from famine at the same age had children and grandchildren with less incidences of heart disease and diabetes.

The study was funded in part by a four-year $882,000 grant from the National Science Foundation.

Now Benoit and Polak are turning their attention to a new study examining the genetic and epigenetic responses of fruit flies that are stressed by parasitic mites.

“The seminal fluid does have a protective role to play for the embryo. You definitely have implications for embryo health and viability. But that’s another chapter,” Polak said.

The researchers also are interested in testing whether parasitic infection could change the quality of male seminal plasma, possibly exerting effects on the embryo as they observed in the diet study.

After spending most of his academic career studying them, Polak has respect for the lowly fruit fly.

“You get a special sort of appreciation for them when you see them in your kitchen courting on a piece of fruit,” he said. “You know a lot about them – and maybe you’re a little less likely to swat them.”

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Connie’s comments: Whole foods, exercise, avoidance of toxins and quality supplementation are important for both mother and father to have healthy offspring.

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