Friday, June 13, 2008
This is Spinal Tap - Dendritic Spines
The picture at right is truly amazing. It overlays three color-coded images of dendritic spines in a living mouse's brain, collected 45 minutes apart. White regions indicate stable dendritic segments. Green shows spines that retracted and red shows spines that sprouted during the observation period.
From A New Window to View How Experiences Rewire the Brain: Howard Hughes Medical Institute researchers have developed sophisticated microscopy techniques that permit them to watch how the brains of live mice are rewired as the mice learn to adapt to new experiences.
Their studies show that rewiring of the brain involves the formation and elimination of synapses, the connections between neurons. The technique offers a new way to examine how learning can spur changes in the organization of neuronal connections in the brain.
“Our first observations of the large-scale structure of neurons, their axons and dendrites, revealed that they were remarkably stable over a month.” Dendrites and axons are highly branched structures, where dendrites are the input side of neurons and axons the output side.
“However, when we zoomed in closer, we found that some spines on dendrites appeared and disappeared from day to day,” said Svoboda. These spines stipple the surface of dendrites, like twigs from a branch, and form the receiving ends of synapses, which are the junctions between neurons where neurotransmitters are released.
“This finding was quite unexpected, because the traditional view of neural development has been that when animals mature, the formation of synapses ceases, which is indicated by stable synaptic densities,” said Svoboda. “However, the flaw in this view has been that a stable density only indicates a balanced rate of birth and death of synapses. It doesn’t imply the absence of the formation of new synapses, but it was often interpreted that way.”
In their experiments, Svoboda and his colleagues observed that about twenty percent of spines disappeared from one day to the next, offset by the formation of new spines.
“While we were surprised at the rate of turnover of some spines, we were also surprised at the incredible stability of other spines,” said Svoboda. The spines appeared to fall into different classes. And while there were those that turned over rapidly, other spines, typically the larger ones, persisted for months.
For this post, I've pulled together a lot of different articles on dendritic spines. They are amazingly complex, and are remarkably self-sufficient - they've got local mitochondria for powering their cellular machinery, can not only locally assemble proteins but also control the structure of the proteins that are to be assembled there, and can control their shape to help preserve long term memories...
From ScienceDaily (Dec. 22, 2004): Compared with most cells, neurons are more elongated and complex. Neurons are divided into different sections: the long, thin axon and the branching, tree-like dendrites that receive signals from other neurons via the suction cup-shaped synapses. Synapses, tiny gaps separating neurons, consist of a presynaptic ending at the very tip of an axon that contains neurotransmitters, a postsynaptic ending that contains neurotransmitter receptor sites, and the space between the two endings. Both presynaptic and postsynaptic endings require the energy generated by mitochondria.
Critical functions, such as synapses' transmission of information and ability to change rapidly in response to stimuli, are managed by distant cellular compartments that can become isolated from their nearest mitochondria. Sheng and postdoctoral fellow Zheng Li explored whether having the power source far away, like a too-distant room heater, would affect synaptic function.
The researchers looked at mitochrondria in living hippocampal neurons. The hippocampus, a seahorse-shaped brain region in the temporal lobe, is known to play a critical role in memory.
When synapses were stimulated, the researchers found, mitochrondria in the dendrites changed from being long and thin to more aggregated, collecting in globules near the enlarged dendritic spines, as if the mitochondria were reporting for duty at the active part of the neuron.
"Our studies reveal that mitochrondria dynamically redistribute into dendritic protrusions in response to synaptic excitation … The dendritic distribution of mitochondria appears to be an essential and limiting factor for synaptic density and plasticity," the authors wrote. If mitochondria don't migrate into the distant reaches of the dendrites--where most synapses are present--the synapses become less numerous and lose some of their ability to respond to external input. Enhancing mitochondria with the nutrient creatine also promoted synaptic density, the study showed.
ScienceDaily (Jan. 15, 2006): Harvard University biologists have identified a molecular pathway active in neurons that interacts with RNA to regulate the formation of long-term memory in fruit flies. The same pathway is also found at mammalian synapses.
Changes in the dendrites themselves outside of the synaptic region have also been shown to be critical to memory formation. From ScienceDaily (Nov. 3, 2005): Neurons experience large-scale changes across their dendrites during learning, say neuroscientists at The University of Texas at Austin in a new study that highlights the important role that these cell regions may play in the processes of learning and memory.
Dendrites--the thin branch-like extensions of a neuron cell--receive many inputs from other neurons that transmit information through contact points called synapses. Much attention has been focused on the role that changes at synapses play in learning. They change in ways that make it easier for connected neurons to pass information.
Johnston and his colleagues show that learning and memory are likely to not only involve changes at synapses, but also in dendrites. They found that h-channels, which are distributed throughout the dendrite membrane and allow the passage of potassium and sodium ions into and out of the neuron, are altered during learning.
"The h-channels undergo plasticity, not near the synapse but probably throughout the dendritic tree," says Johnston.
To record the changes during learning, cells from the rat hippocampus (an important area of the brain for short-term memory) were electrically stimulated using a high frequency pattern called theta-bursts. Theta-bursts mimic the electrical stimulus that shoots through neurons when animals perform a learning task. The researchers found that when stimulated with theta-bursts, hippocampus neurons showed h-channel plasticity and a rapid increase in the synthesis of h-channel proteins.
The proteins were produced in the rat hippocampal neurons within 10 minutes, which is pretty rapid for cells, says Johnston.
"This really pushes the envelope with respect to how fast a neuron can produce new proteins important for learning," he says.
Learning and memory researchers know that protein synthesis in neurons is related to long-term memory, because protein synthesis inhibitors block long-term memory in animals.
Johnston says it's possible that the new proteins are being used by the neuron to build more h-channels in the dendrite membrane. He has a working hypothesis that h-channels may help buffer receiving neurons from being barraged and over-stimulated by inputs coming from information transmitting neurons.
From the article RNA splicing occurs in nerve cell dendrites: Researchers at the University of Pennsylvania School of Medicine have discovered that nerve-cell dendrites have the capacity to splice messenger RNA (pre-mRNA), a process once believed to only take place in the nucleus of cells.
In the nucleus of a mammalian cell, a gene is copied into mRNA, which possesses both exons (mature mRNA regions destined to code for proteins) and introns (non-coding regions). mRNA splicing works by cutting out introns and merging together the remaining exon pieces, resulting in an mRNA capable of being translated into a specific protein.
The vast array of proteins within the human body arises in part from the many ways that mRNAs can be spliced and reconnected. Specifically, splicing removes pieces of intron and exon regions from the RNA, with the resulting spliced RNA often being made into protein. Should the RNA have different exons spliced in and out of it, then different proteins can be made from this RNA.
Dendrites, which branch from the cell body of the neuron, play a key role in the communication between cells of the nervous system, allowing for many neurons to connect with each other to form a network. Dendrites detect the electrical and chemical signals transmitted to the neuron by the axons of other neurons. The synapse is the neuronal structure where this chemical connection is formed, and investigators surmise that the synapse is where learning and memory occur.
Protein diversity is a key aspect to the complexity of the central nervous system. Proteins are the workhorses of the cell and are generally responsible for insuring that cells function properly. When proteins interact with one another they can elicit specific physiological responses, including the generation and maintenance of memories. Changing protein identity, as can occur with splicing, can change the ability of the protein to interact with other proteins and therefore potentially change such physiological processes. With the dendrite being the initial site in the neuron where learning is thought to occur, the ability to create a diversity of mRNAs, through local splicing, and subsequent protein translation may permit exquisitely sensitive control of these cellular functions.
"The regulation and timing of the expression of proteins is what makes the central nervous system function," says Eberwine. The diversity and redundancy of the nervous-system proteins may serve to help maintain the system over a lifetime. However, failure in protein regulation or proper expression in neurons may give rise to cognitive dysfunction. "Most neurodegenerative and psychiatric illnesses exhibit dendrite dysfunction, therefore, the inability to properly generate spliced RNAs in dendrites or proteins may underlie aspects of these disease processes."
From ScienceDaily (Sep. 24, 2007): A molecular "recycling plant" permits nerve cells in the brain to carry out two seemingly contradictory functions -- changeable enough to record new experiences, yet permanent enough to maintain these memories over time. Michael Ehlers of Duke University Medical Center has done a study that shows the importance of receptor recycling in the dendritic spines plays in maintaining memories. "This process occurs on a time scale of minutes or hours, so the acquisition of new neurotransmitter receptors and their recycling is an on-going process. Memory loss may result from receptors escaping from the synapse. ... We believe that the existence of this recycling ability explains in part how individual dendritic spines retain their unique identity amidst this constant molecular turnover," Ehlers said. "The system is simultaneously dynamic and stable. ... If the receptors don't get recycled, you see a gradual loss of synaptic function that is associated with reduced cognitive ability," Ehlers said. "These dendritic spines are where learning and memories reside. These are the basic units of memory." (See the post on Clathrin - the super cool cellular transport machine for more information on receptor recycling.)
From Establishing Synaptic Independence: How Neurons Create Diffusional Barriers by Bernardo Sabatini: The optimal diffusional isolation of each spine likely depends on the state of the associated synapse. For example, at certain times the synapse may need to exchange components with the dendrite, requiring a relatively open neck. At other times, it may be beneficial to constrict the neck and favor the accumulation of plasticity-inducing molecules in the spine head. We found that the strength of diffusional coupling across the neck is a dynamically regulated parameter that is adjusted in response to changes in activity levels. Furthermore, the diffusional isolation of each synapse is controlled by a local signaling loop, such that when a synapse and the postsynaptic cell are consistently coactive, the neck of the spine that houses the active synapse is rapidly constricted. Since these patterns of activity are known to induce strengthening of hippocampal synapses, we propose that adjusting the properties of the neck may titrate the threshold for plasticity induction by determining the lifetimes of plasticity-inducing molecules near active synapses.
Synapses in a State: A Molecular Mechanism to Encode Synaptic History and Future Synapse Function by Johanna Montgomery
Dynamin-dependent NMDAR endocytosis during LTD and its
dependence on synaptic state discusses the idea of synaptic state
Posted by Brian at 11:09 PM