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Pregnancy Timeline by SemestersFetal liver is producing blood cellsHead may position into pelvisBrain convolutions beginFull TermWhite fat begins to be madeWhite fat begins to be madeHead may position into pelvisImmune system beginningImmune system beginningPeriod of rapid brain growthBrain convolutions beginLungs begin to produce surfactantSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
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Home | Pregnancy Timeline | News Alerts |News Archive July 28, 2014

LEFT: Granule cells connect with other cells via long projections (dendrites).
UPPER RIGHT: Actual synapses are located on thorn-like protuberances called "spines”.
LOWER RIGHT: Spines are shown in green in this computer reconstruction.
Image Source: Michaela Müller, PhD, DZNE-German Center for Neurogenerative Diseases

 






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Two proteins 'pulse' information into memory

Neuroscientists in Germany have succeeded in providing new insights on the link between nerve cells as the interface to the hippocampus and stored memory.

Researchers at the German Center for Neurogenerative Diseases (DZNE) and the German Cancer Research Center (DKFZ) analyzed tissue samples from mice to identify two molecular proteins as they act upon the brain’s memory center — ‘CKAMP44’ and ‘TARP Gamma-8’. These proteins have similar counterparts in humans and are known to form protein complexes with AMPA receptors which transmit signals to the hippocampus.

AMPA receptors are found in ‘granule’ cells located in the cerebellum and are among the smallest neurons in the brain — and the most numerous averaging around 50 billion — which means they make up about 3/4 of the brain's neurons. They are packed into a thick layer at the bottom of the cerebellar cortex.

Granule cell bodies are packed into a thick layer at the bottom
of the cerebellar cortex. Each cell has only four to five dendrites.


Their results have been published in the journal Neuron.


Brain function depends on communication between nerve cells, neurons, which are woven together in a dense network. Neurons constantly relay signals to one another without making direct contact. An extremely narrow gap, known as the synapse, separates them.

Receptors bind to neurotransmitters — chemicals produced within the cell and located at the tip of an axon — to trigger an electrical impulse in the neuron.

Receptors
are molecular structures located on a neuron’s outer shell specifically to receive neural signals via neurotransmitters.


A team led by Dr. Jakob von Engelhardt, focused on AMPA receptors as they bind glutamate neurotransmitters which are particularly common in the brain. Dr. von Engelhard: “We looked at AMPA receptors in an area of the brain, which is the main entrance to the hippocampus — a region responsible for learning and memory formation. Among other things the hippocampus processes and combines sensory perception.”


“We found AMPA receptors exert a significant influence on the functioning of glutamate receptors. Then we identified that the ability of a nerve cell to receive signals isn’t solely dependent on its receptors; CKAMP44 and TARP Gamma-8 are just as important.”

Dr. Jakob von Engelhardt, with DZNE and DKFZ


The researchers discovered, among other things, that both proteins promote the transport of glutamate receptors to the cell surface. “This means they influence how receptive the nerve cell is to incoming signals,” says von Engelhardt. The group also found the two proteins have different effects: TARP Gamma-8 ensures more AMPA receptors are integrated into the synapse gap, while CKAMP44 does not.


“Synapse gaps alter their transmission ability depending on their plasticity. TARP Gamma-8 increases long-term plasticity. It makes the cell able to strengthen synaptic communication over a prolonged time-period.

“This stable condition may last for hours, days or even longer. This long-term effect is essential for the creation of memories. We can only remember things if the connections between neurons are long-lasting.”

Dr. Jakob von Engelhardt, with DZNE and DKFZ


The research team had discovered that the proteins affect how quickly AMPA receptors return to a receptive state. “If glutamate has docked on to a receptor, it takes a while until the receptor can react to the next neurotransmitter. CKAMP44 lengthens this period. But TARP Gamma-8 helps the receptor to return to a receptive state more quickly.” added von Engelhardt.

Therefore, CKAMP44 temporarily weakens the synaptic connection, while TARP Gamma-8 strengthens it. Through this interplay of these two proteins, synapse is able to tune its sensitivity. Tuning can last from milliseconds to a few seconds before the strength of the connection is again changed. Specialists refer to this as “short-term plasticity.”

“These proteins ultimately influence how well the nerve cell is able to react in rapid succession to incomming signals,” added Dr. von Engelhardt

Much to the researchers’ surprise, it turned out that the two proteins influence not only the synapse but also the shape of neurons. In the absence of these two protein molecules, neurons have fewer dendrites to establish contact with other neurons.

Since the two molecules act directly on the structure as well as function of synapse gaps on granule cells, Dr. von Engelhardt considers it very likely that they also have an influence on learning and memory.

Highlights
•CKAMP44 and TARP γ-8 increase surface expression of AMPA receptors
•Both proteins can be contained within the same AMPA receptor complex
•They both influence neuronal morphology
•Short- and long-term synaptic plasticity is differentially modulated by both proteins

Summary
Gating properties and surface trafficking of AMPA receptors (AMPARs) are modulated by auxiliary subunits. Here we studied the function of coexpressed auxiliary subunits belonging to two different classes. We focused on TARP γ-8 and CKAMP44 in dentate gyrus (DG) granule cells, since both subunits are highly expressed in this cell type. TARP γ-8 and CKAMP44 decrease the rate of deactivation but have an opposing influence on receptor desensitization, which accounts for their differential modulation of synaptic short-term plasticity. Furthermore, long-term plasticity (LTP) requires TARP γ-8 but not CKAMP44. The coexpression of both auxiliary subunits is necessary for the efficient targeting of AMPARs to the cell surface of DG granule cells. Finally, electrophysiological and biochemical evidence support the notion that CKAMP44 and TARP γ-8 can be contained in the same AMPAR complex.

Original publication
Co-expressed auxiliary subunits exhibit distinct modulatory profiles on AMPA receptor function.
Konstantin Khodosevich, Eric Jacobi, Paul Farrow, Anton Schulmann, Alexandru Rusu, Ling Zhang, Rolf Sprengel, Hannah Monyer, Jakob von Engelhardt. Neuron (2014). doi:10.1016/j.neuron.2014.07.004.

A video abstract is availbale at
http://youtu.be/YHT0a7DEuHs

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