(Image caption: Neurons with the Unc5-receptor send their axons in a cell culture in all directions. The processes avoid the parallel orientated stripes containing the FLRT3-protein (red). Credit: ©Seiradake et al, Neuron 2014)

Navigation for nerve cells

During brain development, the precursors of nerve cells sometimes have to migrate long distances from their place of origin to their destination. In this process, proteins, such as FLRTs (pronounced “flirts”), act as guide molecules. Researchers at the Max Planck Institute of Neurobiology in Martinsried, together with colleagues at the Universities of Oxford and Frankfurt have now discovered that FLRT proteins on the surface of progenitor cells can induce repellent and attractant signals depending on its binding partner. The scientists used X-ray crystallography to reveal the structural bases for both FLRT-mediated adhesion and repulsion. They applied this knowledge to elucidate how these opposed signals control cellular migration. Which signal predominates depends on the particular type of cell migration. The results further show that FLRTs also exert attractant and repellent effects in the walls of blood vessels and therefore control the development of other tissue types as well.

Pyramidal cells are the central nerve cells in the cerebral cortex. During embryonic development, the precursors of pyramidal cells follow the paths of glial cell axons to migrate from their original location to the surface of the cerebral cortex. As soon as they reach their intended layer, they develop into mature pyramidal cells and interlink to form a functional network. Pyramidal cells also spread to a limited extent within these layers, though the importance of such tangential migration is still poorly understood.

This migration of precursor pyramidal cells is controlled by FLRTs (fibronectin-leucine-rich transmembrane proteins) located on the cell surface. According to the researchers at the Max Planck Institute in Martinsried, FLRTs and the Unc5 receptor form a group of guidance proteins with opposing effects on cell migration. On one hand, they act as a repellent. This is the case when a FLRT molecule binds to an Unc5 receptor on the surface of a progenitor cell. “In this way, as the precursor cell migrates radially, it receives a signal to continue migrating at an adjusted speed to not move prematurely into outer layers,” explains Rüdiger Klein from the Max Planck Institute of Neurobiology.

However, if two identical FLRT molecules bind to each other, this triggers an adhesive signal. The scientists’ results show that pyramidal cells are guided in this manner as they spread tangentially, without affecting their ability to find their target layer. Thus, there are proteins with attractant and repellent effects located on the surface of precursor pyramidal cells. “By integrating these opposing signals, cells can navigate through brain tissue. During radial migration FLRTs induce repulsion; during tangential dispersion FLRT attraction dominates,” says Klein.

In their study the scientists also investigated whether the mechanisms of FLRT adhesion and repulsion are present in other cell types. Their findings show that cells in the walls of blood vessels in the retina and the umbilical cord are also controlled by a combination of attractant and repellent signals modulated by FLRT and Unc5 proteins.

(Image caption: A neuron in which the axon originates at a dendrite. Signals arriving at this dendrites become more efficiently forwarded than signals input elsewhere. Credit: Alexei V. Egorov, 2014)

Communication without detours

Certain nerve cells take a shortcut for the transmission of information: signals are not conducted via the cell`s center, but around it like on a bypass road. The previously unknown nerve cell shape is now presented in the journal “Neuron" by a research team from Heidelberg, Mannheim and Bonn.

Nerve cells communicate by using electrical signals. Via widely ramified cell structures—the  dendrites—, they receive signals from other neurons and then transmit them over a thin cell extension—the axon—to other nerve cells. Axon and dendrites are usually interconnected by the neuron’s cell body. A team of scientists at the Bernstein Center Heidelberg-Mannheim, Heidelberg University, and the University of Bonn has now discovered neurons in which the axon arises directly from one of the dendrites. Similar to taking a bypass road, the signal transmission is thus facilitated within the cell.

“Input signals at this dendrite do not need not be propagated across the cell body,” explains Christian Thome of the Bernstein Center Heidelberg-Mannheim and Heidelberg University, one of the two first authors of the study. For their analyses, the scientists specifically colored the places of origin of axons of so-called pyramidal cells in the hippocampus. This brain region is involved in memory processes. The surprising result: “We found that in more than half of the cells, the axon does not emerge from the cell body, but arises from a lower dendrite,” Thome says.

The researchers then studied the effect of signals received at this special dendrite. For this purpose, they injected a certain form of the neural transmitter substance glutamate into the brain tissue of mice that can be activated by light pulses. A high-resolution microscope allowed the neuroscientists to direct the light beam directly to a specific dendrite. By the subsequent activation of the messenger substance, they simulated an exciting input signal.

“Our measurements indicate that dendrites that are directly connected to the axon, actively propagate even small input stimuli and activate the neuron,” says second first author Tony Kelly, a member of the Sonderforschungsbereich (SFB) 1089 at the University of Bonn. A computer simulation of the scientists predicts that this effect is particularly pronounced when the information flow from other dendrites to the axon is suppressed by inhibitory input signals at the cell body.

“That way, information transmitted by this special dendrite influences the behavior of the nerve cell more than input from any other dendrite,” Kelly says. In a future step, the researchers attempt to figure out which biological function is actually strengthened through the specific dendrite—and what therefore might be the reason for the unusual shape of these neurons.

Blocking brain’s ‘internal marijuana’ may trigger early Alzheimer’s deficits

When incoming signals to the pyramidal tract build to high intensity, pyramidal cells adapt by becoming more inclined to fire than they normally are. This phenomenon, which neuroscientists call plasticity, is thought to underpin learning and memory. It ensures that volleys of high-intensity input — such as might accompany falling into a hole, burning one’s finger with a match, suddenly remembering where you buried the treasure or learning for the first time how to spell “cat” — are firmly stored in the brain’s memory vaults and more accessible to retrieval.

These intense bursts of incoming signals are the exception, not the rule. Pyramidal nerve cells constantly receive random beeps and burps from upstream nerve cells — effectively, noise in a highly complex, electrochemical signaling system. This calls for some quality control. Pyramidal cells are encouraged to ignore mere noise by another set of “wet blanket” nerve cells called interneurons. Like the proverbial spouse reading a newspaper at the kitchen table, interneurons continuously discourage pyramidal cells’ transmission of impulses to downstream nerve cells by steadily secreting an inhibitory substance — the molecular equivalent of yawning, eye-rolling and oft-muttered suggestions that this or that chatter is really not worth repeating to the world at large, so why not just shut up.

Passing along the message

But when the news is particularly significant, pyramidal cells squirt out their own “no, this is important, you shut up!” chemical — endocannabinoids — which bind to specialized receptors on the hippocampal interneurons, temporarily suppressing them and allowing impulses to continue coursing along the pyramidal cells to their follow-on peers.

A-beta is known to impair pyramidal-cell plasticity. But Madison’s research team showed for the first time how it does so. Small clusters consisting of just a few A-beta molecules render the interneuron’s endocannabinoid receptors powerless, leaving inhibition intact even in the face of important news and thus squashing plasticity.

While small A-beta clusters have been known for a decade to be toxic to nerve cells, this toxicity requires relatively long-term exposure, said Madison. The endocannabinoid-nullifying effect the new study revealed is much more transient. A possible physiological role for A-beta in the normal, healthy brain, he said, is that of supplying that organ’s sophisticated circuits with yet another, beneficial layer of discretion in processing information. Madison thinks this normal, everyday A-beta mechanism run wild may represent an entry point to the progressive and destructive stages of Alzheimer’s disease.

Exactly how A-beta blocks endocannabinoids’ action is not yet known. But, Madison’s group demonstrated, A-beta doesn’t stop them from reaching and binding to their receptors on interneurons. Rather, it interferes with something that binding ordinarily generates. (By analogy, turning the key in your car’s ignition switch won’t do much good if your battery is dead.)

Madison said it would be wildly off the mark to assume that, just because A-beta interferes with a valuable neurophysiological process mediated by endocannabinoids, smoking pot would be a great way to counter or prevent A-beta’s nefarious effects on memory and learning ability. Smoking or ingesting marijuana results in long-acting inhibition of interneurons by the herb’s active chemical, tetrahydrocannabinol. That is vastly different from short-acting endocannabinoid bursts precisely timed to occur only when a signal is truly worthy of attention.

“Endocannabinoids in the brain are very transient and act only when important inputs come in,” said Madison, who is also a member of the interdisciplinary Stanford Bio-X institute. “Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It’s like listening to five radio stations at once.”

Besides, flooding the brain with external cannabinoids induces tolerance — it may reduce the number of endocannabinoid receptors on interneurons, impeding endocannabinoids’ ability to do their crucial job of opening the gates of learning and memory.

Mapping blank spots in the cheeseboard maze

IST Austria Professor Jozsef Csicsvari together with collaborators succeeds in uncovering processes in which the formation of spatial memory is manifested in a map representation • Researchers investigate timescale of map formation • Inhibitory interneurons possibly involved in selection of map

During learning, novel information is transformed into memory through the processing and encoding of information in neural circuits. In a recent publication in Neuron, IST Austria Professor Jozsef Csicsvari, together with his collaborator David Dupret at the University of Oxford, and Joseph O’Neill, postdoc in Csicsvari’s group, uncovered a novel role for inhibitory interneurons in the rat hippocampus during the formation of spatial memory.

During spatial learning, space is represented in the hippocampus through plastic changes in the connections between neurons. Jozsef Csicsvari and his collaborators investigate spatial learning in rats using the cheeseboard maze apparatus. This apparatus contains many holes, some of which are selected to hide food in order to test spatial memory. During learning trials, animals learn where the rewards are located, and after a period sleep, the researchers test whether the animal can recall these reward locations. In previous work, they and others have shown that memory of space is encoded in the hippocampus through changes in the firing of excitatory pyramidal cells, the so-called “place cells”. A place cell fires when the animal arrives at a particular location. Normally, place cells always fire at the same place in an environment; however, during spatial learning the place of their firing can change to encode where the reward is found, forming memory maps.

In their new publication, the researchers investigated the timescale of map formation, showing that during spatial learning, pyramidal neuron maps representing previous and new reward locations “flicker”, with both firing patterns occurring. At first, old maps and new maps fluctuate, as the animal is unsure whether the location change is transient or long-lasting. At a later stage, the new map and so the relevant new information dominates.

The scientists also investigated the contribution of inhibitory interneuron circuits to learning. They show that these interneurons, which are extensively interconnected with pyramidal cells, change their firing rates during map formation and flickering: some interneurons fire more often when the new pyramidal map fires, while others fire less often with the new map. These changes in interneuron firing were only observed during learning, not during sleep or recall. The scientists also show that the changes in firing rate are due to map-specific changes in the connections between pyramidal cells and interneurons. When a pyramidal cell is part of a new map, the strengthening of a connection with an interneuron causes an increase in the firing of this interneuron. Conversely, when a pyramidal cell is not part of a new map, the weakening of the connection with the interneuron causes a decrease in interneuron firing rate. Both, the increase and the decrease in firing rate can be beneficial for learning, allowing the regulation of plasticity between pyramidal cells and controlling the timing in their firing.

The new research therefore shows that not only excitatory neurons modify their behaviour and exhibit plastic connection changes during learning, but also the inhibitory interneuron circuits. The researchers suggest that inhibitory interneurons could be involved in map selection – helping one map dominate and take over during learning, so that the relevant information is encoded.

Hippocampal Pyramidal Neurons Comprise Two Distinct Cell Types that Are Countermodulated by Metabotropic Receptors

Relating the function of neuronal cell types to information processing and behavior is a central goal of neuroscience. In the hippocampus, pyramidal cells in CA1 and the subiculum process sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information, which they transmit throughout the brain. Do these cells constitute a single class or are there multiple cell types with specialized functions? Using unbiased cluster analysis, we show that there are two morphologically and electrophysiologically distinct principal cell types that carry hippocampal output. We show further that these two cell types are inversely modulated by the synergistic action of glutamate and acetylcholine acting on metabotropic receptors that are central to hippocampal function. Combined with prior connectivity studies, our results support a model of hippocampal processing in which the two pyramidal cell types are predominantly segregated into two parallel pathways that process distinct modalities of information.