Ұзақ мерзімді депрессия: Нейрондық байланыстардың әлсіреуі және оның механизмдері

In neurophysiology, long term depression (LTD) is an activity dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress. As the opposing process to long term potentiation (LTP), LTD is one of several processes that serves to selectively weaken specific synapses in order to make constructive use of synaptic strengthening caused by LTP. This is necessary because, if allowed to continue increasing in strength, synapses would ultimately reach a ceiling level of efficiency, which would inhibit the encoding of new information. Both LTD and LTP are forms of synaptic plasticity.

LTD in the hippocampus and cerebellum have been the best characterized, but there are other brain areas in which mechanisms of LTD are understood. Hippocampal/cortical LTD can be dependent on NMDA receptors, metabotropic glutamate receptors (mGluR), or endocannabinoids. The result of the underlying LTD molecular mechanism in cerebellum is the phosphorylation of AMPA glutamate receptors and their elimination from the surface of the parallel fiber Purkinje cell (PF PC) synapse.

It is highly important for neurons to maintain a variable range of neuronal output. If synapses were only reinforced by positive feedback, they would eventually come to the point of complete inactivity or too much activity. To prevent neurons from becoming static, there are two regulatory forms of plasticity that provide negative feedback: metaplasticity and scaling. Metaplasticity is expressed as a change in the capacity to provoke subsequent synaptic plasticity, including LTD and LTP. The Bienenstock, Cooper and Munro model (BCM model) proposes that a certain threshold exists such that a level of postsynaptic response below the threshold leads to LTD and above it leads to LTP. BCM theory further proposes that the level of this threshold depends upon the average amount of postsynaptic activity. Scaling has been found to occur when the strength of all of a neuron’s excitatory inputs are scaled up or down. LTD and LTP coincide with metaplasticity and synaptic scaling to maintain proper neuronal network function.

Long term depression can be described as either homosynaptic plasticity or heterosynaptic plasticity. Homosynaptic LTD is restricted to the individual synapse that is activated by a low frequency stimulus. In other words, this form of LTD is activity dependent, because the events causing the synaptic weakening occur at the same synapse that is being activated. Homosynaptic LTD is also associative in that it correlates the activation of the postsynaptic neuron with the firing of the presynaptic neuron. LTD occurs at these synapses when Schaffer collaterals are stimulated repetitively for extended time periods (10–15 minutes) at a low frequency (approximately 1 Hz). When Ca2+ entry is below threshold, it leads to LTD. The threshold level in area CA1 is on a sliding scale that depends on the history of the synapse. If the synapse has already been subject to LTP, the threshold is raised, increasing the probability that a calcium influx will yield LTD. In this way, a "negative feedback" system maintains synaptic plasticity. Change in voltage provides a graded control of postsynaptic Ca2+ by regulating NMDAR dependent Ca2+ influx, which is responsible for initiating LTD. While LTP is in part due to the activation of protein kinases, which subsequently phosphorylate target proteins, LTD arises from activation of calcium dependent phosphatases that dephosphorylate the target proteins. Selective activation of these phosphatases by varying calcium levels might be responsible for the different effects of calcium observed during LTD. LTD is involved in predictive control exerted by cerebellar circuitry and cerebellar reserve.

Further research has determined calcium's role in long term depression induction. While other mechanisms of long term depression are being investigated, calcium's role in LTD is a defined and well understood mechanism by scientists. High calcium concentrations in the post synaptic Purkinje cells is a necessity for the induction of long term depression. There are several sources of calcium signaling that elicit LTD: climbing fibres and parallel fibres which converge onto Purkinje cells. Calcium signaling in the post synaptic cell involved both spatial and temporal overlap of climbing fibre induced calcium release into dendrites as well as parallel fibre induced mGluRs and IP3 mediated calcium release. In the climbing fibres, AMPAR mediated depolarization induces a regenerative action potential that spreads to the dendrites, which is generated by voltage gated calcium channels. Paired with PF mediated mGluR1 activation results in LTD induction. In the parallel fibres, GluRs are activated by constant activation of the parallel fibres which indirectly induces the IP3 to bind to its receptor (IP3) and activate calcium release from intracellular storage. In calcium induction, there is a positive feedback loop to regenerate calcium for long term depression. Climbing and parallel fibres must be activated together to depolarize the Purkinje cells while activating mGlur1s. Timing is a critical component to CF and PF as well, a better calcium release involves PF activation a few hundred milliseconds before CF activity. In this form of LTD, low frequency stimulation of one pathway results in LTD only for that input, making it homosynaptic. The magnitude of this LTD is comparable to that which results from low frequency stimulation, but with fewer stimulation pulses (40 PPS for 900 low frequency stimulations).

Computational models predict that LTD creates a gain in recognition memory storage capacity over that of LTP in the perirhinal cortex, and this prediction is confirmed by neurotransmitter receptor blocking experiments.

Spike timing dependent plasticity (STDP) refers to the timing of presynaptic and postsynaptic action potentials. STDP is a form of neuroplasticity in which a millisecond scale change in the timing of presynaptic and postsynaptic spikes will cause differences in postsynaptic Ca2+ signals, inducing either LTP or LTD. LTD occurs when postsynaptic spikes precede presynaptic spikes by up to 20 50 ms. Whole cell patch clamp experiments "in vivo" indicate that post leading pre spike delays elicit synaptic depression. There is a plasticity window: if the presynaptic and postsynaptic spikes are too far apart (i. e., more than 15 ms apart), there is little chance of plasticity. The possible window for LTD is wider than that for LTP – although it is important to note that this threshold depends on synaptic history. When postsynaptic action potential firing occurs prior to presynaptic afferent firing, both presynaptic endocannabinoid (CB1) receptors and NMDA receptors are stimulated at the same time. Postsynaptic spiking alleviates the Mg2+ block on NMDA receptors. The postsynaptic depolarization will subside by the time an EPSP occurs, enabling Mg2+ to return to its inhibitory binding site. Thus, the influx of Ca2+ in the postsynaptic cell is reduced. CB1 receptors detect postsynaptic activity levels via retrograde endocannabinoid release. STDP selectively enhances and consolidates specific synaptic modifications (signals), while depressing global ones (noise). This results in a sharpened signal to noise ratio in human cortical networks that facilitates the detection of relevant signals during information processing in humans.

Long term depression has long been hypothesized to be an important mechanism behind motor learning and memory. Cerebellar LTD is thought to lead to motor learning, and hippocampal LTD is thought to contribute to the decay of memory. However, recent studies have found that hippocampal LTD may not act as the reverse of LTP, but may instead contribute to spatial memory formation. Although LTD is now well characterized, these hypotheses about its contribution to motor learning and memory remain controversial. Studies have connected deficient cerebellar LTD with impaired motor learning. In one study, metabotropic glutamate receptor 1 mutant mice maintained a normal cerebellar anatomy but had weak LTD and consequently impaired motor learning. However the relationship between cerebellar LTD and motor learning has been seriously challenged. A study on rats and mice proved that normal motor learning occurs while LTD of Purkinje cells is prevented by (1R 1 benzo thiophen 5 yl 2[2 diethylamino) ethoxy] ethanol hydrochloride (T 588). Likewise, LTD in mice was disrupted using several experimental techniques with no observable deficits in motor learning or performance. These taken together suggest that the correlation between cerebellar LTD and motor learning may have been illusory. Studies on rats have made a connection between LTD in the hippocampus and memory. In one study, rats were exposed to a novel environment, and homosynaptic plasticity (LTD) in CA1 was observed. It suggested that LTD and LTP work together to encode different aspects of spatial memory. New evidence suggests that LTP works to encode space, whereas LTD works to encode the features of space. After chronic cocaine use, the amount of AMPA receptors relative to NMDA receptors decreases in the medium spiny neurons in the NAc shell. Additionally, researchers have recently discovered a new mechanism (which involves LTD) linking soluble amyloid beta protein (Aβ) with the synaptic injury and memory loss related to AD. While Aβ's role in LTD regulation has not been clearly understood, it has been found that soluble Aβ facilitates hippocampal LTD and is mediated by a decrease in glutamate recycling at hippocampal synapses. Excess glutamate is a proposed contributor to the progressive neuronal loss involved in AD. Evidence that soluble Aβ enhances LTD through a mechanism involving altered glutamate uptake at hippocampal synapses has important implications for the initiation of synaptic failure in AD and in types of age related Aβ accumulation. This research provides a novel understanding of the development of AD and proposes potential therapeutic targets for the disease. Further research is needed to understand how soluble amyloid beta protein specifically interferes with glutamate transporters. In the field of research of cerebellum disorders, auto antigens are involved in molecular cascades for induction of LTD of synaptic transmissions between parallel fibers (PFs) and Purkinje cells (PCs), a mechanism of synaptic plasticity in the cerebellum. Anti VGCC, anti mGluR1, and anti GluR delta Abs associated cerebellar ataxias share one common pathophysiological mechanism: a deregulation in PF PC LTD. This causes an impairment of restoration or maintenance of the internal model hold by the cerebellum and triggers cerebellar ataxias. These diseases are LTDpathies. The mechanism of long term depression has been well characterized in limited parts of the brain. However, the way in which LTD affects motor learning and memory is still not well understood. Determining this relationship is presently one of the major focuses of LTD research.

Neurodegenerative diseases research remains inconclusive as to the mechanisms that triggers the degeneration in the brain. New evidence demonstrates there are similarities between the apoptotic pathway and LTD which involves the phosphorylation/activation of GSK3β. NMDAR LTD(A) contributes to the elimination of excess synapses during development. This process is downregulated after synapses have stabilized, and is regulated by GSK3β. During neurodegeneration, there is the possibility that there is deregulation of GSK3β resulting in 'synaptic pruning'. If there is excess removal of synapses, this illustrates early signs of neurodegeration and a link between apoptosis and neurodegeneration diseases.