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In 1949, Canadian psychologist Donald Hebb proposed that "When an axon of cell A is near enough to excite cell b or repeatedly and consistently takes part in firing it, some growth process or metabolic changes take place in one or both cells such that A's efficiency, as one of the cells firing B, is increased". (ref.) This idea is captured in the slogan 'Cells that fire together wire together'. A special set of molecules called neurotrophins play an important role in this. From Joseph LeDoux's book The Synaptic Self: When an action potential occurs in a postsynaptic cell, neurotrophins are released from the cell and diffuse backward across the synapse, where they are taken up by presynaptic terminals. Under the influence of neurotrophins, the terminals begin to branch and sprout new synaptic connections. Since only those presynaptic cells that were just active (that just released transmitter) take up the molecules, only they sprout new connections. activity thus induces growth, and the growth that occurs is restricted to the active terminals.
In addition to this role in the active construction of ciruits, neurotrophins are also involved in synapse selection. The natural fate of may cells during development is an early exit. So-called programmed cell death is one of the regressive events that help shape the final pattern of connectivity. Cell death is prevented if a presynaptic terminal receives a lifes-sustaining shot of neurotrophins from it postsynaptic partner. The survival rate of neurons is in this way regulated by the limited availability of neurotrophins. Only those cells that compete successfully for neurotrophins (those that are active) survive. In the presence of neurotrophins, the surviving terminals (those that were active) alsso begin to sprout new connections. Selection can be a step along the path toward activity-instructed growth -- in other words, selection and instruction are partners in synaptic development.

The image at the top of this post shows undifferentiated cells extending neuronal processes after exposure to neurotrophin delivered from hydrogel coated neural prosthetic devices. This idea of using neurotrophins to efficiently 'wire up' neurons with prosthetic devices is quite intriguing. Let's take a closer look at what neurotrophins are and how they work...

From the Society for Neuroscience article Neurotrophic Factors :
Recent research shows that neurotrophic factors are:
  • Present in early development of the nervous system and are responsible for the initial growth and development of neurons in the peripheral and central nervous systems.

  • Released by target tissue of a growing neuron and can determine whether a neuron reaches its target during development; neurons which do not reach the target die.

  • Capable of making damaged neurons regrow their processes in a test tube and in animal models and, thus, represent exciting possibilities for reversing devastating disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

    Neurotrophic factors, produced by several body tissues including muscle, act by attaching to receptors on the tips, or nerve terminals, and on the cell body -- which contains the nucleus -- of neurons. The signal can then be carried through the axon, the neuron's elongated fiberlike extension, which can be as long as a yard, to the cell body where it tells the cell what to do.
    Thus far, scientists have identified several neurotrophic factor receptors -- which also may be potential targets for therapy. A receptor called trk is required for the action of nerve growth factor (NGF), the first neurotrophic factor, which was discovered 40 years ago. NGF affects primarily neurons using the neurotransmitter acetylcholine in the basal forebrain, sensory neurons and sympathetic neurons that regulate organs such as the heart and lungs. Relatives of trk are receptors for other neurotrophic factors -- trkB seems to be a receptor for brain-derived neurotrophic factor; and trkC for neurotrophin-3.
    In the brain, a neurotrophic factor is released by a neuron or a support cell, such as an astrocyte, and binds to a receptor on a nearby neuron. This binding results in the production of a signal which is transported to the nucleus of the receiving neuron where it results in the increased production of proteins associated with neuronal survival and function.

    From Developmental Biology online" by Scott F. Gilbert:
    The neurotrophin family consists of four members: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Each provides some survival activity on nervous tissue. As mentioned in the text, the final number of neurons innervating a particular organ is attained by thinning the population of neurons through programmed neuronal death. Here, neurotrophic factors secreted by cells in the target field protect the neurons from apoptosis (Korsching, 1993; Lewin and Barde, 1996). Thus, the final number of neurons innervating a target reflects the availability of neurotrophins. The ability of particular neural subsets to respond only to particular neurotrophins can explain the losses of certain peripheral sympathetic neurons in NGF-knockout mice, the deficiency of sensory neurons in BDNF knockout mice, the lack of proprioceptive neurons in NT-3 knockout mice, and the deficiency of particular sensory neurons in NT-4 knockout mice. Neurotrophins also play roles in regulating neuronal plasticity and in regulating the number of neural progenitor cells.

    Neurotrophin receptors

    There are two classes of neurotrophin cell-surface receptors. The p75 receptor (also known as the low-affinity neurotrophin receptor, LANR) is common to all members of the neurotrophin family. The high affinity receptors (having binding constants on the order of 10-11) include receptor tyrosine kinase proteins TrkA, TrkB, and TrkC. These receptors have different specificities for different members of the neurotrophin family TrkA is the receptor for NGF, trkB is the receptor for BDNF and NT-4, and trkC is the receptor for NT-3. However, NT-3 can also bind to trkA and trkB, but with lower affinity than to trkC, and with lower affinity than the primary ligands for these receptors. Similarly, NT-4 also binds to trkA but with lower affinity.

    In addition to these "classical" receptors, the issue is complicated by the existence of isoforms of trkB and trkC, which lack the cytoplasmic tyrosine kinase catalytic region (Barbacid, 1995). These receptors are found throughout the developing body as well, and it is not known if these noncatalytic forms of the receptors act as agonists or inhibitors.

    All four neurotrophins also bind to the low affinity nerve growth factor receptor, p75. The p75 receptor belongs to the tumor necrosis factor receptor family and was the first identified neurotrophin receptor (Johnson et al; 1986). This receptor will bind the neurotrophins, but it has no cytoplasmic tyrosine kinase domain (Chao and Hempstead, 1995; Greene and Kaplan, 1995; Segal and Greenberg, 1996). The roles of this receptor are controversial, as it may also be involved in either promoting or downregulating the response to the neurotrophin. P75 may function to increase the affinity of the trk receptors for their respective neurotrophins, or it may bind the neurotrophins and prevent them from binding to the high affinity receptors. Although it does not have a catalytic intracellular tyrosine kinase domain, it is capable of mediating the neurotrophin signals. The ligand binding of p75 increases the high-affinity TrkA binding sites, enhances TrkA autophosphorylation and selectivity for neurotrophin ligands (Kaplan and Miller, 1997). P75 also increases intracellular ceramide levels and further activates NFk B transcription factor (Carter et al., 1996) and JNK kinase (Casaccia-Bonnefil et al., 1996) independently of tyrosine kinase activity. Conversely, TrkA activation can inhibit p75-mediated signaling, but the mechanism of this inhibition is unclear (Kaplan and Miller, 1997).

    The TrkA neurotrophin receptor has been linked to human diseases. The TrkA gene was originally described as an oncogene in colon cancer (Martin-Zanca et al., 1986) and its translocations are common in papillary thyroid carcinoma (Bongarzone et al., 1989). Recently, a mutation in the TrkA gene was found to cause congenital insensitivity to pain with anhidrosis (CIPA) syndrome (Indo et al., 1996) that closely resembles the phenotype of the TrkA -deficient mice. No disease associations have been described either for the TrkB gene, or the genes for p75NTR or any of the neurotrophins.

    From the abstract for Neurotrophin secretion from hippocampal neurons evoked by long-term-potentiation-inducing electrical stimulation patterns by Annette Gärtner and Volker Staiger: The neurotrophin (NT) brain-derived neurotrophic factor (BDNF) plays an essential role in the formation of long-term potentiation (LTP). Their study found that instantaneous secretion of BDNF is evoked by the same type of action potentials that induce LTP, whereas stimuli that induce Long Term Depression of a neuron do not induce secretion of BDNF.

    Recently, further studies have provided additional details on the workings of BDNF. From Backpropagating Action Potentials Trigger Dendritic Release of BDNF during Spontaneous Network Activity by Nicola Kuczewski et. al: We found that spontaneous backpropagating action potentials, but not synaptic activity alone, led to a Ca2+-dependent dendritic release of BDNF-GFP. Moreover, we provide evidence that endogenous BDNF released from a single neuron can phosphorylate CREB (cAMP response element-binding protein) in neighboring neurons, an important step of immediate early gene activation. Therefore, together, our results support the hypothesis that BDNF might act as a target-derived messenger of activity-dependent synaptic plasticity and development.

    An article in Nature (The Yin and Yang of neurotrophins" by Bai Lu, Petti T. Pang & Newton H. Woo") provides insight into the role played by neurotrophins and how BDNF is synthesized in neurons. From this article, it appears that in some cases, instead of BDNF being released by the dendrites and promoting axonal branching, it instead can be released by the axon and promotes the growth of additional dendritic spines.

    The following picture is a schematic showing the synthesis and sorting of brain-derived neurotrophic factor (BDNF) in a typical neuron.

    First synthesized in the endoplasmic reticulum (ER) (1), proBDNF (precursor of BDNF) binds to intracellular sortilin in the Golgi to facilitate proper folding of the mature domain (2). A motif in the mature domain of BDNF binds to carboxypeptidase E (CPE), an interaction that sorts BDNF into large dense core vesicles, which are a component of the regulated secretory pathway. In the absence of this motif, BDNF is sorted into the constitutive pathway. After the binary decision of sorting, BDNF is transported to the appropriate site of release, either in dendrites or in axons. Because, in some cases, the pro-domain is not cleaved intracellularly by furin or protein convertases (such as protein convertase 1, PC1) (3), proBDNF can be released by neurons. Extracellular proteases, such as metalloproteinases and plasmin, can subsequently cleave the pro-region to yield mature BDNF (mBDNF) (4). MMP, matrix metalloproteinase.

    The last picture in this post (also from (The Yin and Yang of neurotrophins" by Bai Lu, Petti T. Pang & Newton H. Woo") shows the role BDNF plays in promoting the growth of additional dendritic spines and how its absence results in the retraction of dendritic spines:

    a) Molecular cascade of brain-derived neurotrophic factor (BDNF) processing in late-phase long-term potentiation (L-LTP). In response to theta-burst stimulation (TBS), tissue plasminogen activator (tPA) is secreted into the synaptic cleft and cleaves the extracellular protease plasminogen to yield plasmin (1). Plasmin then cleaves proBDNF (the precursor of BDNF, which is released in an activity-dependent manner), yielding mature BDNF (mBDNF) (2). mBDNF binds to TrkB and triggers a series of downstream signalling pathways to induce LTP (3). During the maintenance stage of LTP, mBDNF might be generated by intracellular cleavage after postsynaptic transcription and translation (4). By contrast, proBDNF secreted extracellularly remains uncleaved after low-frequency stimulation (LFS). Uncleaved proBDNF binds to the p75 neurotrophin receptor (p75NTR) (5) to facilitate the induction of long-term depression (LTD), possibly through the regulation of NMDA (N-methyl-D-aspartate) receptor NR2B subunit expression. b) Morphological alterations in synapses induced by pro- and mature BDNF. Left, BDNF–Trk signalling might be an active mechanism that converts activity-induced molecular signals into structural plasticity, contributing to synapse formation. Right, proBDNF–p75NTR signalling might be important in translating activity-dependent signals into negative modulation of structural plasticity, contributing to synapse retraction.

    Some good progress is being made on using neurotrophins to encourage neurons to integrate with medical implants. From EurekAlert (with thanks to the Biosingularity blog): Plastic coatings could someday help neural implants treat conditions as diverse as Parkinson’s disease and macular degeneration.

    The coatings encourage neurons in the body to grow and connect with the electrodes that provide treatment.Jessica O. Winter, assistant professor of chemical and biomolecular engineering at Ohio State University described the research Thursday, August 21 at the American Chemical Society meeting in Philadelphia. She is also an assistant professor of biomedical engineering.

    Worldwide, researchers are developing medical implants that stimulate neurons to treat conditions caused by neural damage. Most research focuses on preventing the body from rejecting the implant, but the Ohio State researchers are focusing instead on how to boost the implants’ effectiveness.

    “We’re trying to get the nerve tissue to integrate with a device — to grow into it to form a better connection,” Winter said.

    She and her colleagues are infusing water-soluble polymers with neurotrophins, proteins that help neurons grow and survive.

    They are combining different polymers, some shaped like tiny spheres and fibers, to create composite coatings that release neurotrophins in a steady dose over time. The coatings also give nerves a scaffold to cling to as they grow around an implant.

    The researchers coated two kinds of electrodes — one, a flat electrode used in retinal implants, and the other a cylindrical electrode array used in deep brain stimulation. The first is being used in experimental treatments for macular degeneration, while the second holds promise for suppressing tremors in people who have Parkinson’s disease.
    So far, however, it appears that the neurite growth achieved in this manner is short-lived. More info on this is available here.
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