Glial cells, including astrocytes and oligodendrocytes, are a focus of research in regenerative medicine because they help neurons stay healthy. If neurons are dying, restoring glial cells could be the key to survival.

ScienceDaily.com, January 28, 2010 — Researchers at the Ludwig Institute for Cancer Research (LICR) at the University of California, San Diego School of Medicine and Moores UCSD Cancer Center have shown one way in which gliomas, a deadly type of brain tumor, can evade drugs aimed at blocking a key cell signaling protein, epidermal growth factor receptor (EGFR),that is crucial for tumor growth. In a related finding, they also proved that a particular EGFR mutation is important not only to initiate the tumor, but for its continued growth or “maintenance” as well.

The findings, which appear during the week of January 18 in an online early edition of the Proceedings of the National Academy of Sciences, provide both new insights into the behavior of gliomas as well as potential new drug targets and treatment strategies.

“The results suggest that the expression of EGFR is required for tumors to keep growing, and we’ve shown for the first time that there are mechanisms that the tumor is using to circumvent the need for the receptor,” said Frank Furnari, PhD, associate professor of medicine at the UCSD School of Medicine and associate investigator at the San Diego branch of the LICR, adding that other cancers may use similar tactics. “We need to find out more about the signaling pathways that brain tumors use to get around targeted therapeutics, such as those directed at EGFR.”

In aggressive gliomas, extra copies of the EGFR gene are produced, and half of such tumors also carry an EGFR mutation, which ramps up tumor growth and portends a poor prognosis. Clinical trials of anti-EGFR agents have been disappointing; brain tumors may respond initially, but later become resistant to the drugs. To better understand why, Furnari, Webster Cavenee, PhD, professor of medicine and director of San Diego’s LICR branch, and their group wanted to find out if the mutant EGFR was needed by tumors for their continued growth.

The team — including postdoctoral fellows Akitake Mukasa, MD, PhD, and Jill Wykosky, PhD — created a genetic system in mice in which they could control the expression of mutated EGFR, turning it off and on with the drug tetracycline. They found that the tumors’ growth would stop for a period of time when tetracycline blocked EGFR, much like what is seen in patients who respond to EGFR inhibitors. But the tumors would start to grow again, even without EGFR, meaning something else was driving tumor growth.

The researchers examined individual tumors that had sidestepped or “escaped” the need for mutant EGFR to sustain their growth. In some cases, tumors that would normally have killed mice in 20 days were stable for months with the blocked expression of mutant EGFR. The scientists used microarray technology to test for genes that had not been previously expressed in the tumors but were now overexpressed in tumors that no longer required EGFR. They finally found one, KLHDC8 which, when inhibited, halted tumor growth.

“That finding makes us think that this gene would be a reasonable target,” Cavenee said. “About half of the individual tumors that didn’t need mutant EGFR to grow expressed that gene and, if we silenced the gene, those tumors did not grow.”

Cavenee thinks this could be a model for the behavior of other tumors. “If the tumors use the same strategy to get around receptor inhibitors, then targeting that alternate pathway plus the receptor up front should give a longer response because it’s hitting the primary event plus the escape route,” he said.

Now the research team is searching for other genes expressed in tumors that can escape EGFR dependence, and looking for biological pathways that might be involved.

Other contributors include: Keith L. Ligon, MD, PhD, Dana-Farber Cancer Institute, and Lynda Chin, MD, Dana-Farber and Brigham and Women’s Hospital.

Funding support came from the SUMITOMO Life Social Welfare Services Foundation, The Paul Taylor American Brain Tumor Association, the National Institutes of Health, the National Foundation for Cancer Research and the Goldhirsh Foundation.

Glioma
Classification and external resources

Brain: Glioma: Gross; fixed tissue, horizontal section brain stem and cerebellum with obvious gelatinous appearing neoplasm a pontine glioma. Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

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Neurons and their communication

Most cells in the nervous system are of two fundamentally different types: neurons and glial cells. This post is mostly about the communication of information between neurons and each other as well as muscles and organs.

It was only after our discovery and understanding of electricity that we discovered that muscle movement is mediated by the flow of electricity along nerve fibers.

Neurons and glial cells

Membrane potential

Membrane potential is the difference in electrical charge between the inside and outside of a cell. This was first demonstrated in the intercellular recordings of axons by Alan Hodgkin and Andrew Huxley in 1939 experiment with squid giant axon. Unusually large axons are useful for eneration of escape reflexes as they conduct more quickly.

They demonstrated that axons at rest are electically polarized, with a Resting Membrane Potential of approximately -60mV/-70 mV (i.e. compared to the outside). it is fundamental to setting off spikes by opening certain ion channels.

  • You can check/record the MP you can use the tip of an electrode inside the neuron and compare it with the extracellular fluid outside the neuron
  • The voltage is always charged negatively inside an alive cell i.e. -70mV or -90mV
  • There are selective, semi-permuable channels in the membranes

In a biological membrane, the Reversal potential (also known as the Nernst potential) of an ion is the membrane potential at which there is no net (overall) flow of ions from one side of the membrane to the other. In the case of post-synaptic neurons, the reversal potential is the membrane potential at which a given neurotransmitter causes no net current flow of ions

Concentration ratio (amount) of ions is unimportant. The voltage potential decides when ions leak out of channel. If more voltage outside -> membrane potential takes place. Different ion channels have particular target voltages.

The Nernst Equation

The equilibrium potential is determined by 4 things:

  1. The concentration of ion inside and outside of the cell
  2. The temperature of the solution
  3. The valence of the ion
  4. The amount of work required to separate a given quantity of change

The equation that describes the equilibrium potential was formed by a physical chemist called Walter Nernst (1888):

E (ion) is the membrane potential at which the ionic species is at the equilibrium. R is gas constant, T temperature, F is Faraday’s constant, Z the valence of the ion, while ion/ion are the concentration of the ion outside and inside the cell.

Neurotransmitters

Neurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse. Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may follow graded electrical potentials.

Excitatory and inhibitory Neurotransmitters

The only direct effect of a neurotransmitter is to activate one or more types of receptors. The effect on the postsynaptic cell depends, therefore, entirely on the properties of those receptors.

Some neurotransmitters (for example, Glutamate), the most important receptors all have excitatory effects: that is, they increase the probability that the target cell will fire an action potential.

Other neurotransmitters (such as GABA), the most important receptors all have inhibitory effects.

There are, however, other neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory receptors exist; and there are some types of receptors that activate complex metabolic pathways in the postsynaptic cell to produce effects that cannot appropriately be called either excitatory or inhibitory. Thus, it is an oversimplification to call a neurotransmitter excitatory or inhibitory—nevertheless it is so convenient to call glutamate excitatory and GABA inhibitory that this usage is seen very frequently.

Action Potential

An AP is generated by the rapid influx of Na+ ions followed by a slightly slower efflux of K+ ions. Although the generation of an AP does not disrupt the concentration gradients of these ions across their membrane, the movement of charge is sufficient to generate a large and brief deviation in the membrane potential.

Propagation of the AP along the axon allows communication of the output of the cell to its synapses. Neurons posses many different types of ionic channels in their membranes, allowing complex patterns of action potential to be generated and complex synaptic computations to occur within single neurons.

The Action Potential of Neurons

Action potentials play multiple roles in several types of excitable cells such as neurons, myocytes, and electrocytes. The best known action potentials are pulse-like waves of voltage that travel along axons of neurons.

A.P are used in long distance communication i.e. 1 long neuron in giraffe’s neck. Spikes are calculated in all or nothing sense (they either occur or not). Bigger axons carry out A.P faster i.e. so small preys can escape faster.

  • When Cell is stimulated, permeability of cell membrane changes, and this alters distribution of charge in the cell body
  • Voltage gated channels on the membrane open / close depending on the voltage changes in the membrane (closed when no stimulant)
  • A stimulus polarizes the membrane and this opens up Na+ / sodium channels to open, Na+ ions rush in to the cell
  • Cell becomes + inside and – outside 5. Na+ channel close while K+ / potassium channel opens and K+ rushes out
  • Cell returns to being + outside and – inside 7. K+ channel close 8. Membrane polarity changes along the membrane
  • This repeats and AP spreads, and AP travels down the neuron like a wave

Snapshot of AP would include:

  1. Membrane capacitance discharging
  2. Na+ channels opening
  3. K+ channels opening Na+ (Sodium) and K+ (potassium) ion channels.

Myline capacitance and Saltatory conduction

One important electrical property of neurons is their capacitance in their cell membranes, which is the electrical insulator and non-conductor capacity of neurons.

A neurons capacitance is proportional to its membrane surface area, so large neurons, have larger capacitances. Capacitance also decreases with the distance between the two conducting surfaces.

Saltatory conduction is the process by which the myelin propagate rapid conduction of action potentials down the axon, their capacitance not only increases the membrane resistance of the axon in myelinated areas of the node of ranvier, but also increases the distance between the conducting surfaces, decreasing the membrane capacitance.

Cable Theory

Cable theory can be used to explain the current flow in axons. Although it was developed in 1855 to model the transatlantic telegraph cable, it was only used to describe action potentials in 1946 by Hodgkin and Rushton.

The current is the product of a conductance and a voltage difference. The conductance is that of the ion channels which are opened by the presynaptic neuron and they are therefore time-dependent (or, more precisely, dependent on the state of the presynaptic neuron). The voltage difference is the difference between the present voltage and the reversal potential of the ion species which can pass through the channel. For an excitatory synapse, the reversal potential will be higher than the resting potential, for an inhibitory synapses, it will be lower.

The neuron is treated as an electrically passive, perfectly cylindrical transmission cable, which can be described by a partial differential equation.

In here V(x, t) is the voltage across the membrane at a time t and a position x along the length of the neuron, and where λ and τ are the characteristic length and time scales on which those voltages decay in response to a stimulus. These scales can be determined from the resistances and capacitances per unit length.

Cable theory’s simplified view of a neuronal fiber. The connected RC circuits correspond to adjacent segments of a passive neurite. The extracellular resistances re (the counterparts of the intracellular resistances ri) are not shown, since they are usually negligibly small; the extracellular medium may be assumed to have the same voltage everywhere.

Post-Synaptic Potential

Communication between Neurons – Neurotransmitters transition at the synaptic cleft.

PPs are changes in the membrane potential of the postsynaptic terminal of a chemical synapse. Postsynaptic potentials are graded potentials, and should not be confused with action potentials although their function is to initiate or inhibit action potentials. They are caused by the presynaptic neuron releasing neurotransmitters from the terminal button at the end of an axon into the synaptic cleft. The neurotransmitters bind to receptors on the postsynaptic terminal, which may be a neuron or a muscle cell in the case of a neuromuscular junction. These are collectively referred to as postsynaptic receptors, since they are on the membrane of the postsynaptic cell. Neurotransmitters bind to their receptors by having a particular shape or structure, somewhat like the way a key fits into certain locks.

  1. Neurotransmitters are stored in (pre-)synaptic vesicles at end of axon (of the pre-synaptic cell/neuron)
  2. As AP reaches terminal end of an axon, Ca+ influx through Ca+ channels, causes these vesicles to diffuse with pre-synaptic membrane
  3. Neuro transmitters go across the synaptic cleft, and diffuse bind to specific receptors, and act for a temporary time
  4. NT action is terminated by reuptake pumps that force them back in to the axon terminals or by enzymes and terminates their effect at the post-synaptic membrane

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How Memories Are Made, And Recalled

Artist’s rendering of neuron activity. Researchers have recorded the activity of hundreds of individual neurons making memories. (Credit: iStockphoto/Sebastian Kaulitzki)

UCLA — What makes a memory? Single cells in the brain, for one thing.

For the first time, scientists at UCLA and the Weizmann Institute of Science in Israel have recorded individual brain cells in the act of calling up a memory, thus revealing where in the brain a specific memory is stored and how the brain is able to recreate it.

Reporting in the current online edition of the journal Science, Dr. Itzhak Fried, senior study author and a UCLA professor of neurosurgery, and colleagues recorded the activity of hundreds of individual neurons making memories in the brains of 13 epilepsy patients being treated surgically at UCLA Medical Center.

Surgeons had placed electrodes in the patients’ brains to locate the origin of their seizures before surgical treatment — standard procedure in such cases. Fried made use of the same electrodes to record neuron activity as memories were being formed.

The patients watched several video clips of short duration, including such things as landmarks and people, along with other clips of Jerry Seinfeld, Tom Cruise, “Simpsons” character Homer Simpson and others. As the patients watched, the researchers recorded the activity of many neurons in the hippocampus and a nearby region known the entorhinal cortex that responded strongly to individual clips.

A few minutes later, after performing an intervening task, the patients were asked to recall whatever clips came to mind.

“They were not prompted to recall any specific clips,” Fried said, “but to use ‘free recall’ — that is, whatever popped into their heads.”

The researchers found that the same neurons that had responded earlier to a specific clip fired strongly a second or two before the subject reported recalling that clip. These neurons did not fire, however, when other clips were recalled. Ultimately, it was possible for the researchers to know which clip a patient was recalling before the patient announced it.

Fried noted that the single neurons that were recorded as they fired were not acting alone but were part of a much larger memory circuit of hundreds of thousands of cells caught in the act of responding to the clips.

The study is significant, he said, because it confirms for the first time that spontaneous memories arise through the activity of the very same neurons that fired when the memory was first being made. This link between reactivation of neurons in the hippocampus and conscious recall of past experience has been suspected and theorized for sometime, but the study now provides direct evidence for such a link.

“In a way, then,” Fried said, “reliving past experience in our memory is the resurrection of neuronal activity from the past”

Other authors of the study included first author Hagar Gelbard-Sagiv, Michal Harel and Rafael Malach of the Weizmann Institute and UCLA postdoctoral scholar Roy Mukamel.

The research was funded by the U.S. National Institute of Neurological Disorders and Stroke, as well as the Israel Science Foundation and the U.S.–Israel Binational Science Foundation.

And……………

Beauty Through The Eye Of The Microscope

Starlike astrocytes and other so-called glial cells serve as scaffolding for the
billions of neurons that make possible memory and the human mind. The brain of a newborn human has 100 billion nerve cells. A baby’s billions of neurons are supported by about a trillion glial cells, which account for 90% of the cells in the human brain.

Glial cells are vital in the efficient transmission of messages between nerve cells. Science shows us hidden images that can be exquisitely beautiful and often resemble abstract painting, such as the microscopic picture of the human nerve cell shown at left. Thus, that which enables us to perceive and appreciate beauty is, by itself, a work of art.

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