A relatively new line of research for helping paralyzed patients, including those with ALS, to communicate and retain a degree of self-sufficiency is called brain-computer interface BCI technology and is illustrated in Figure This technology sounds like something out of science fiction: it allows paralyzed patients to control a computer using only their thoughts.
There are several forms of BCI. Some forms use EEG recordings from electrodes taped onto the skull. These recordings contain information from large populations of neurons that can be decoded by a computer. Other forms of BCI require the implantation of an array of electrodes smaller than a postage stamp in the arm and hand area of the motor cortex. This form of BCI, while more invasive, is very powerful as each electrode can record actual action potentials from one or more neurons.
These signals are then sent to a computer, which has been trained to decode the signal and feed it to a tool—such as a cursor on a computer screen. This means that a patient with ALS can use e-mail, read the Internet, and communicate with others by thinking of moving his or her hand or arm even though the paralyzed patient cannot make that bodily movement. Recent advances have allowed a paralyzed locked-in patient who suffered a stroke 15 years ago to control a robotic arm and even to feed herself coffee using BCI technology.
Despite the amazing advancements in BCI technology, it also has limitations. The technology can require many hours of training and long periods of intense concentration for the patient; it can also require brain surgery to implant the devices. Watch this video in which a paralyzed woman use a brain-controlled robotic arm to bring a drink to her mouth, among other images of brain-computer interface technology in action.
Synapses are not static structures. They can be weakened or strengthened. They can be broken, and new synapses can be made. Synaptic plasticity allows for these changes, which are all needed for a functioning nervous system. In fact, synaptic plasticity is the basis of learning and memory. Two processes in particular, long-term potentiation LTP and long-term depression LTD are important forms of synaptic plasticity that occur in synapses in the hippocampus, a brain region that is involved in storing memories.
Long-term potentiation LTP is a persistent strengthening of a synaptic connection. LTP is based on the Hebbian principle: cells that fire together wire together. There are various mechanisms, none fully understood, behind the synaptic strengthening seen with LTP. These receptors are normally blocked by magnesium ions; however, when the postsynaptic neuron is depolarized by multiple presynaptic inputs in quick succession either from one neuron or multiple neurons , the magnesium ions are forced out allowing Ca ions to pass into the postsynaptic cell.
So, the next time glutamate is released from the presynaptic membrane, it will have a larger excitatory effect EPSP on the postsynaptic cell because the binding of glutamate to these AMPA receptors will allow more positive ions into the cell. The insertion of additional AMPA receptors strengthens the synapse and means that the postsynaptic neuron is more likely to fire in response to presynaptic neurotransmitter release.
Some drugs of abuse co-opt the LTP pathway, and this synaptic strengthening can lead to addiction. In this situation, calcium that enters through NMDA receptors initiates a different signaling cascade, which results in the removal of AMPA receptors from the postsynaptic membrane, as illustrated in Figure The decrease in AMPA receptors in the membrane makes the postsynaptic neuron less responsive to glutamate released from the presynaptic neuron.
The weakening and pruning of unused synapses allows for unimportant connections to be lost and makes the synapses that have undergone LTP that much stronger by comparison. Neurons have charged membranes because there are different concentrations of ions inside and outside of the cell.
Voltage-gated ion channels control the movement of ions into and out of a neuron. When a neuronal membrane is depolarized to at least the threshold of excitation, an action potential is fired. The action potential is then propagated along a myelinated axon to the axon terminals. In a chemical synapse, the action potential causes release of neurotransmitter molecules into the synaptic cleft.
Through binding to postsynaptic receptors, the neurotransmitter can cause excitatory or inhibitory postsynaptic potentials by depolarizing or hyperpolarizing, respectively, the postsynaptic membrane.
In electrical synapses, the action potential is directly communicated to the postsynaptic cell through gap junctions—large channel proteins that connect the pre-and postsynaptic membranes. Synapses are not static structures and can be strengthened and weakened. Two mechanisms of synaptic plasticity are long-term potentiation and long-term depression.
The neurotransmitter travels across the synapse to excite or inhibit the target neuron. Different types of neurons use different neurotransmitters and therefore have different effects on their targets.
Synapse — The junction between the axon of one neuron and the dendrite of another, through which the two neurons communicate. QBI newsletters Subscribe. Help QBI research Give now. Skip to menu Skip to content Skip to footer.
Site search Search. Site search Search Menu. Action potentials and synapses. Home The Brain Brain functions. Co-activation of postsynaptic dopamine D2-type receptors D2R enhances endocannabinoid production and the subsequent induction of presynaptic LTD, mediated through activation of presynaptic CB1 receptors CB1R.
From Kreitzer and Malenka, LTD in the cerebellum was also reported to depend on retrograde endocannabinoid signaling Safo and Regehr, , but the mechanistic basis for this observation is still unclear, since, as discussed above, cerebellar LTD is expressed postsynaptically. Metaplasticity refers to a higher-order form of synaptic plasticity in which synaptic activity, which by itself does not directly affect synaptic efficacy, leads to a persistent change in the direction or magnitude of subsequent activity-dependent synaptic plasticity.
The best-studied examples of metaplasticity are those in which prior activity shifts the threshold for LTP and LTD induction. A potential functional role for metaplasticity has been demonstrated by modifying the level of activity during the development of the visual cortex in vivo Philpot et al, , , As discussed below, such changes in synaptic plasticity may importantly contribute to the experience-dependent plasticity of ocular dominance following manipulation of the visual environment.
Theoretically, without additional stabilizing mechanisms, activity-dependent forms of plasticity such as LTP and LTD could drive neural circuit activity towards epileptogenic excitation or complete quiescence. Synaptic scaling is considered a form of homeostatic plasticity that counters potentially maladaptive effects of long-term synapse-specific plasticity by globally affecting the transmission through all synapses on a given neuron Turrigiano and Nelson, In terms of its basic properties and underlying mechanisms, this form of synaptic plasticity contrasts dramatically with the forms of LTP and LTD we have discussed thus far.
Decreased activity due to blockade of synaptic transmission or spiking causes an increase in the strength of all excitatory synapses onto excitatory neurons, whereas increased activity generally induced by partially blocking inhibitory synapses reduces the strength of all excitatory synapses Turrigiano et al, Importantly, the relative strengths of individual synpases appear to be maintained even though global synaptic input is significantly altered. Relatively little is known about the molecular mechanisms underlying synaptic scaling other than it involves changes in the number of AMPARs and NMDARs at individual synapses Perez-Otano and Ehlers, ; Turrigiano and Nelson, ; Watt et al, and likely presynaptic changes as well Burrone and Murthy, ; Burrone et al, Recently, evidence has been presented supporting a role for secreted factors in the induction of homeostatic plasticity, suggesting that key triggers for this form of plasticity may not be cell autonomous.
In addition, there is evidence suggesting a role for secreted BDNF in driving the opposite form of synaptic scaling; the decrease in synaptic strengths caused by extended periods of increased network acitivity Rutherford et al, ; Turrigiano, Although LTP and LTD are prime candidate mechanisms underlying many different forms of experience-dependent plasticity, it is important to remember that they are experimental phenomena used to examine how different patterns of activity can elicit bidirectional control over synaptic strength.
Establishing a causal connection between a specific form of synaptic plasticity and the behavioral consequences of specific experiences remains a daunting task.
Nevertheless, over the last decade, significant advances have been made in connecting synaptic plasticity to a number of different types of adaptive experience-dependent plasticity. Furthermore, it has become increasingly clear that understanding the mechanisms of synaptic plasticity may provide important insights into the pathophysiology of a variety of neuropsychiatric disorders and also point the way toward novel therapeutic approaches.
In the following sections, we will briefly provide examples that demonstrate that LTP and LTD do occur in vivo in response to experience and may play a causal role in mediating the consequences of experience. Given that LTP was first described in the hippocampus, a structure well established to be critically important for declarative memory Squire et al, , it is not surprising that over the last three decades there has been a major effort aimed at demonstrating a role for hippocampal LTP in encoding new memories Martin et al, ; Morris, Correlations have been observed between defective hippocampal synaptic plasticity and defective hippocampal-dependent memory tasks upon perturbation of a number of proteins which function in synaptic plasticity, either pharmacologically, or through gene knockout Lynch, ; Martin et al, ; Morris, Recently, more compelling evidence for a role of synaptic plasticity in hippocampal-dependent learning has been presented.
During an inhibitory avoidance task, LTP could be recorded in vivo in a subset of hippocampal CA1 pyramidal cells Whitlock et al, This demonstrated that the patterns of activity generated during a real learning task were sufficient to elicit LTP.
These findings strongly suggest that maintained LTP was required for the engram that stored the key spatial information. In addition to its role as a key component of the mechanisms underlying the encoding of declarative memories, hippocampal NMDAR-dependent LTP as well as LTD may provide important insights into the pathophysiology and potential treatment of major mental illnesses.
For example, a leading hypothesis for the pathophysiology of schizophrenia posits a dysfunction in glutamatergic synapses, in particular a hypofunction of NMDARs Coyle and Tsai, ; Javitt, ; McCullumsmith et al, ; Tamminga, Thus, understanding the signaling events downstream of NMDAR activation may provide important insights into this devastating disease.
Another example of the potential importance of studying LTP and LTD comes from investigation into the therapeutic mechanisms of drugs used to treat bipolar disorder. Drugs such as lithium, valproate, and lamotrigine have been reported to have significant effects on the phosphorylation of AMPAR subunits and affect their surface expression Du et al, , , ; Gray et al, These findings suggest that these drugs may somehow tap into the same mechanisms that have evolved to generate LTP and LTD and also point to novel approaches for the development of new therapeutic agents that may prove efficacious for treatment of this illness.
Sensory receptive fields in the cortex are modified by early postnatal experience and the link between synaptic plasticity and these forms of experience-dependent plasticity in sensory systems is becoming increasingly established Foeller and Feldman, ; Karmarkar and Dan, ; Malenka and Bear, For example, a strong connection between synaptic plasticity and experience-dependent plasticity has been established in the visual system during the shift in ocular dominance caused by monocular deprivation MD Foeller and Feldman, ; Karmarkar and Dan, ; Malenka and Bear, Furthermore, in vivo recordings demonstrated that MD caused a rapid decrease in the visually evoked potential VEP from the deprived eye and a slower enhancement of the VEP from the open eye Frenkel and Bear, Importantly, completely blocking activity in the deprived eye prevented the depression of the VEP demonstrating that this depression required retinal activity and, like LTD, was therefore activity-dependent Frenkel and Bear, This appears to be due to alterations in the patterns of pre- and postsynaptic spiking in vivo in a manner that is ideal for generating spike-timing-dependent LTD Celikel et al, LTP mechanisms, on the other hand, appear to be important for the strengthening of synapses in developing barrel cortex due to early postnatal experience.
In vivo experience drives recombinant GluR1 into barrel cortex synapses in a manner similar to that which occurs during NMDAR-dependent LTP, whereas expression of a short peptide that inhibits delivery of endogenous AMPARs blocks the experience-dependent increase in synaptic strength Takahashi et al, as does a dominant-negative form of the synaptic scaffold protein PSD Ehrlich and Malinow, Thus, as predicted by theoretical considerations Bienenstock et al, ; Stent, , LTP and LTD mechanisms appear to be critically involved in early neural circuit development and it is not difficult to imagine how disruption in these mechanisms might contribute to a host of neurodevelopemental disorders such as autism Geschwind and Levitt, ; Rubenstein and Merzenich, Pavlovian fear conditioning is a form of associative memory that depends on the amygdala for its induction and maintenance Sigurdsson et al, It occurs when a neutral stimulus such as a tone is temporally paired with a strong noxious stimulus such as an electric shock creating a memory trace, the consequences of which are that the neutral stimulus elicits the learned fear response.
Considerable evidence is consistent with the hypothesis that LTP at sensory inputs to the lateral nucleus of the amygdala is necessary and perhaps sufficient for establishing this engram Sigurdsson et al, Importantly, fear conditioning induces synaptic potentiation at these synapses, and this increase in synaptic strength occludes further induction of LTP McKernan and Shinnick-Gallagher, ; Rogan et al, ; Tsvetkov et al, NMDARs in the amgydala are also involved in the extinction of learned fear, which can be conceptualized as a different form of learning Myers and Davis, Furthermore, acute treatment with D -cycloserine, a partial agonist of NMDARs, enhances the learning processes that are responsible for fear extinction via actions in the amygdala Walker et al, On the basis of these observations, clinical trials have been initiated using D -cycloserine in combination with behavioral therapy to enhance the extinction of fear in phobic patients Hofmann et al, ; Otto et al, ; Ressler et al, Results to date suggest that the administration of D -cycloserine either before or shortly after exposure to fearful cues does in fact enhance the extinction of the anxiety previously associated with specific cues.
Thus, the study of the neural substrates of learned fear and its extinction is a compelling example of how research on the mechanisms of synaptic plasticity has directly led to a potential novel treatment for common psychiatric disorders. The defining characteristic of drug addiction is persistent and compulsive seeking and ingestion of drugs despite adverse consequences.
Over the last decade, a leading hypothesis has been that an important neural substrate of addiction, in particular relapse, is long-term associative memory processes occurring in several neural circuits that receive input from midbrain dopamine neurons Everitt and Robbins, ; Hyman et al, In other words, it is thought that addictive drugs can usurp the normal adaptive mechanisms underlying reward-based learning.
The most well-established key site of action of addictive drugs is the mesolimbic dopamine system consisting of the VTA and the NAc. Excitatory synaptic transmission in these structures is critical for mediating several forms of long-lasting, drug-induced behavioral plasticity Everitt and Wolf, ; Hyman and Malenka, It, therefore, has been reasonable to hypothesize that plasticity at these synapses plays an important role in mediating some of the behavioral consequences of exposure to drugs of abuse Wolf, Furthermore, administration of a single dose of several different classes of drugs of abuse causes a significant increase in synaptic strength at excitatory synapses onto dopamine cells in the VTA Faleiro et al, ; Saal et al, ; Ungless et al, In addition, conditioned place preference, as well as the synaptic potentiation that is observed following cocaine administration, are impaired in GluR1 knockout mice Dong et al, , with the caveat that these mice still exhibit robust behavioral sensitization in response to repeated exposure to psychostimulants Dong et al, ; Vekovischeva et al, Consistent with a functional role for this LTD in addiction, injection of glutamate receptor antagonists into the NAc abolishes the expression of behavioral sensitization Kelley, Recently, it has also been reported that cocaine self-administration abolishes the ability to induce LTD in the core of the NAc after prolonged 21 days abstinence Martin et al, and in vivo administration of tetrahydrocannabinol THC or cocaine impairs the generation of eCB-LTD Fourgeaud et al, ; Mato et al, ; Robbe et al, b.
Thus, drugs of abuse may elicit certain forms of synaptic plasticity in specific circuits while simultaneously impairing plasticity in other circuits. Synaptic plasticity in the dorsal striatum has also been correlated with certain learned behaviors, in particular in motor control Gubellini et al, ; Pisani et al, Indirect pathway medium spiny neurons MSNs project to the lateral globus pallidus and primarily express D2 dopamine receptors while direct pathway MSNs project to the substantia nigra and express D1 dopamine receptors.
However, in slices from dopamine-depleted animals, indirect pathway eCB-LTD can be rescued by a D2 receptor agonist or pharmacological inhibitors of endocannabinoid degradation.
Remarkably, administration of these drugs together in vivo dramatically reduces Parkinsonian motor deficits suggesting that endocannabinoid-mediated depression of indirect pathway synapses has a critical role in motor control and may be a valuable target for therapy of striatal-based brain disorders Kreitzer and Malenka, This works also points out the potential power of examining the mechanisms of synaptic plasticity and placing them in the context of the neural circuits in which they are found.
We have attempted to briefly review the enormous field of synaptic plasticity research in a concise and accessible manner so that by the end of this article, readers will have a reasonably up to date knowledge of current thinking about the mechanisms underlying the major forms of synaptic plasticity in the mammalian brain and a sense of what their in vivo functions might be.
By necessity we have had to leave out important topics such as how synaptic activity modulates NMDAR-mediated synaptic responses eg, Morishita et al, , inhibitory synaptic responses Chevaleyre et al, , or the intrinsic excitability of neurons Xu and Kang, ; Zhang and Linden, , all of which will have profound effects on neural circuit function.
Furthermore, several compelling examples that correlate long-term synaptic plasticity with experience-dependent modifications in behavior have been left out, such as the role of cerebellar LTD in motor learning Boyden et al, ; Ito, ; Jorntell and Hansel, This review should also make clear that while extensive progress has been made, much remains unknown.
Even for the most established forms of plasticity, NMDAR-dependent LTP and LTD in the CA1 region of the hippocampus, we still know little about the details of the signal transduction pathways triggering these forms of plasticity and which specific proteins are being modified to cause the changes in synaptic efficacy.
We also know little about the molecular mechanisms underlying the structural changes in synapses that seem to accompany LTP and LTD. With the accumulation of evidence demonstrating that long-term synaptic modifications do in fact play important roles in a host of adaptive brain functions, we believe there is strong justification to continue efforts toward establishing the detailed molecular basis of the various forms of synaptic plasticity.
This is particularly important because, as we have tried to make clear, such knowledge is likely to have a major impact on our understanding and treatment of a wide range of brain disorders. What direction do we envision the field taking in the near future? By definition, synaptic plasticity is an electrophysiological phenomenon. Only by recording synaptic responses can the investigator be sure that synaptic function has been modified.
Until relatively recently, most electrophysiological studies depended on pharmacological manipulations of proteins, an approach that was aided by the use of genetically modified mice. Indeed, a close interdependence has emerged between electrophysiologists and cell biologists and this has dramatically impacted the field.
Thus, electrophysiologists are increasingly making use of tools that enable overexpression, knockdown, and molecular replacement of target proteins both in vitro and in vivo eg, Schluter et al, These advances are enabling a true molecular dissection of the mechanisms underlying plasticity of mammalian brain synapses.
Recent advances in high-throughput technologies, such as gene-chip microarrays for mRNA profiling and advanced mass spectrometry for identification of multiple proteins in a mixed population, have enabled the identification of the molecular components of many biological phenomena and contributed significantly to understanding their regulation. These advances have so far only lightly impacted the field of synaptic plasticity Pocklington et al, , but we envision that they will have increasing influence in the near future, despite the technical difficulties that are encountered when trying to apply these approaches to the inherently complex preparations used in the study of synaptic plasticity.
What might we gain from such studies? A clearer picture of the molecules which participate in the processes underlying the different forms of synaptic plasticity, and the dynamics of their activation and interactions, would enable the formulation of much more sophisticated models of the events underlying the triggering, expression, and maintenance of specific forms of synaptic plasticity.
This in turn would create a strong foundation for focused efforts aimed at identifying the central pathways mediating synaptic plasticity and assaying their relevance to the phenomenon measured electrophysiologically. By combining electrophysiological, molecular, cell biological and proteomic approaches, we envision that the next few decades will bring further clarification of the detailed molecular mechanisms underlying the major forms of synaptic plasticity that we have discussed in this review.
The use of more sophisticated molecular and genetic manipulations, in particular, the development of mouse lines with highly restricted expression of transgenes that can be turned on or off with fine temporal control, will simultaneously facilitate the examination of the neural circuit basis of behavior. Together, we believe these approaches will allow sophisticated manipulation of synaptic plasticity mechanisms in highly restricted neural circuits and thereby greatly advance our understanding of how synaptic plasticity mediates both adaptive and pathological experience-dependent plasticity.
Applying these same approaches to disease models should yield new insights into the molecular pathology of diseases of the synapse such as addiction, schizophrenia, and Alzheimer's diseases and also pave the way toward the development of novel and more efficacious treatments.
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