User:Patrick.Raab.1/Long-term Depression First Draft

Long-term depression (LTD), in neurophysiology, is the weakening of a neuronal synapse that lasts from hours to days. It results from either strong synaptic stimulation (as occurs in the cerebellar Purkinje cells) or persistent weak synaptic stimulation (as in the hippocampus). Long-term potentiation (LTP) is the opposing process. LTD is thought to result from changes in postsynaptic receptor density, although changes in presynaptic release may also play a role. Cerebellar LTD has been hypothesized to be important for motor learning. However, it is likely that other plasticity mechanisms play a role as well. Hippocampal LTD may be important for the clearing of old memory traces. Hippocampal/cortical LTD can be dependent of NMDA receptors, metabotrophic glutamate receptors (mGluR) or endocannabinoids. LTD is distinct from synaptic depotentiation, which is the reversal of long-term potentiation. LTD is a novel reduction in synaptic strength - specifically, an activity-dependent reduction in the excitatory post-synaptic potential compared to the baseline level.

LTD is one of several processes that serves to selectively weaken explicit sets of synapses in order to make constructive use of synaptic strengthening caused by LTP. This is because, if allowed to continue increasing in strength, synapses would ultimately reach a peak level of efficiency, which would inhibit the encoding of new information.

Long-term Depression and Neural Homeostasis
It is very important for neurons to maintain a variable range of neuronal output. If synapses were only reinforced by positive feedback, synapses 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. Scaling has been found to occur when the strength of all 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 The Bienenstock, Cooper and Munro model (BMC model) proposes that a certain threshold exists such that a level of post-synaptic response below the threshold leads to LTD and above leads to LTP. BMC theory further proposes that the level of this threshold depends upon the average amount of post synaptic activity.

Homosynaptic LTD
Homosynaptic LTD is restricted to the individual synapse that is activated by a low frequency stimulus.

Heterosynaptic LTD
Heterosynaptic LTD occurs at synapses that are not potentiated or are inactive. This form of LTD impacts synapses nearby those receiving action potential.

Associative LTD
Associative LTD is characterized by the collective presynaptic and postsynaptic increase in intracellular calcium levels.

In the Hippocampus
LTD affects hippocampal synapses between the Schaffer collaterals and the CA1 pyramidal cells. For an LTD to occur at these synapses, Schaffer collaterals must be stimulated repetitively for extended time periods (10-15 minutes) at a low frequency (approximately 1 Hz). Depressed EPSPs result from this particular stimulation pattern. The type of calcium signal in the postsynaptic cell largely determines whether LTD or LTP occurs; LTD is brought about by small, slow rises in postsynaptic calcium levels. Activation of NMDA-type glutamate receptors, which belong to a class of ionotropic glutamate receptors (iGluRs), is required for calcium entry into the CA1 postsynaptic cell. 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. The activation of postsynaptic phosphatases causes internalization of synaptic AMPA receptors (also a type of iGluRs) into the postsynaptic cell by clathrin-coated endocytosis mechanisms, thereby reducing sensitivity to glutamate released by Schaffer collateral terminals.

In the Cerebellum
LTD occurs at synapses in cerebellar Purkinje neurons, which receive two forms of excitatory input known as climbing fibers and parallel fibers. LTD decreases the efficacy of parallel fiber synapse transmission, though, according to recent findings, it also impairs climbing fiber synapse transmission. Both parallel fibers and climbing fibers must be simultaneously activated for LTD to occur. In one pathway, parallel fiber terminals release glutamate to activate AMPA and metabotropic glutamate receptors in the postsynaptic Purkinje cell. When the glutamate binds to the AMPA receptor, the membrane depolarizes. Glutamate binding to the metabotropic receptors, however, produces diacylglycerol (DAG) and inositol triphosphate (IP3) second messengers. In the pathway initiated by activation of climbing fibers, calcium enters the postsynaptic cell through voltage-gated ion channels, raising intracellular calcium levels. Together, DAG and IP3 augment the calcium concentration rise by targeting IP3-sensitive triggering release of calcium from intracellular stores as well as protein kinase C (PKC) activation (which is accomplished jointly by calcium and DAG). PKC phosphorylates AMPA receptors, causing receptor internalization as is seen in hippocampal LTD. With the loss of AMPA receptors, the postsynaptic Purkinje cell response to glutamate release from parallel fibers is depressed.

In the Visual Cortex
Long Term Depression has also been observed in the visual cortex. Recurring low-frequency stimulation of layer IV of the visual cortex or the white matter of the visual cortex causes LTD in layer III. In this form of LTD, low-frequency stimulation of one pathway resulted in LTD only for that input, making this type of LTD homosynaptic. This type of LTD is similar to that found in the Hippocampus, it is triggered by a small elevation in postsynaptic calcium ions and activation of phosphatase.

Spike Timing-Dependent Plasticity (STDP)
STDP refers to the timing of presynaptic and postynaptic action potentials (spikes). STPD is a form of nueral plasticity in which millisecond-scale timing changes in presynaptic and postsynapic spikes can induce LTP and LTD. LTD occurs when postsynaptic spikes lead 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. LTP is induced when the neurotransmitter release occurs 5-15ms before a back-propagating action potential, and LTD is induced when the stimulus occurs 5-15ms after the bAP. There is a plasticity window: if the pre-synaptic and post-synaptic spikes are too far apart (i.e. more than 15ms apart), there is little chance of plasticity. The possible window for LTD is wider than that for LTP - although 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. CB1 receptors detect postsynaptic activity levels by retrograde endocannabinoid release, while presynaptic NMDA receptors sense presynaptic spiking. Initial spiking alleviates the Mg2 block on NMDA receptors, whereas further spiking causes the collection of glutamate around the axon terminal and the activation of presynaptic NMDA receptors.

Postsynaptic Calcium Influx and LTD
Calcium influx in a neuron can cause both LTP and LTD, depending on the timing and frequency of the input The Bienenstock, Cooper and Munro model (BCM model - 1982) explains how the type of Ca2+ signal leads to both LTP and LTD. They postulate that when there is a low calcium influx, it leads to LTD, and a Ca2+ entry above threshold leads to LTP. The threshold level is on a sliding scale, and 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, it provides a "negative feedback" system to maintain synaptic plasticity.

Ca2+ influx via voltage gated calcium channels (VGCCs) plays an important role in the induction of homosynaptic LTD. LTD is susceptible to manipulations that alter levels of postsynaptic Ca2+ in dendrites.

Associative LTD is dependent on the activation of VGCCs by postsynaptic action potentials. Since the Ca2+ influx through N-type channels is highly regulated, it is a preferred target for neuromodulation by various neurotransmitters such as GABA, glutamate, serotonin, somatostatin, and adenosine. As a result, the recruitment of N-type channels may determine whether the postsynaptic Ca2+ signal is below or above the threshold for LTD induction. Fluorescent imaging studies further indicate that Ca2+ influx via high-threshold L- and R- type VGCCs occurs only when somatic action potentials are generated. The blockage of VGCCs prevents LTD induction.

The Lisman Model
John Lisman proposed that the concentrations of intracellular Ca2+ have a critical role in determining whether long-term potentiation (LTP) or long-term depression is elicited. This model provides explanation for how the activation of the NMDA (N-methyl-d-aspartate) receptor can both cause depression or potentiation of synaptic transmission. The onset of LTD is a result of weak activation of the NMDA receptor, causing low level increases in Ca2+. Low levels of Ca2+ will result in the activation of the protein phosphatase, calcineurin. Since calcineurin has a greater affinity for Ca2+ then competing protein kinases, it undergoes preferential activation and is responsible for dephosphorylating substrates, resulting in the induction of LTD. Strong activation of the NMDA receptor results in elevated Ca2+ levels and the induction of LTP. The increased concentration of Ca2+ enables the activation of CaMKII and PKC. However, strong NMDA receptor activation results in a feedback inhibition mechanism, preventing LTD.

Role of Endocannabinoids
Endocannabinoids affect long-lasting plasticity processes in various parts of the brain, serving both as regulators of pathways and necessary retrograde messengers in specific forms of LTD. In regard to retrograde signaling, endocannabinoid receptors (CB1) function widely throughout the brain in presynaptic inhibition. Endocannabinoid retrograde signaling has been shown to effect LTD at corticostriatal synapses and glutamatergic synapses in the prelimbic cortex of the nucleus accumbens (NAc), and it is also involved in spike-timing-dependent LTD in the visual cortex. Endocannabinoids are implicated in LTD of inhibitory inputs (LTDi) within the basolateral nucleus of the amygdala (BLA) as well as in the stratum radiatum of the hippocampus. Additionally, endocannabinoids play an important role in regulating various forms of synaptic plasticity. They are involved in inhibition of LTD at parallel fiber Purkinje neuron synapses in the cerebellum and NMDA receptor dependent LTD in the hippocampus.

The Role of Long-term Depression in Motor learning and Memory
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. 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 maintain a normal cerebellar anatomy but have weak LTD and consequently impaired motor learning. However, another 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).

Studies on rats have made a connection between LTD and memory. In one study, rats were exposed to a novel environment and homosynaptic LTD in CA1 was observed. After the rats were brought back to their initial environment, LTD activity was lost. It was found that if the rats are exposed to novelty the electrical stimulation required to depress synaptic transmission is of lower frequency than without novelty. When the rat is put in a novel environment, acetylcholine is released in the hippocampus from medial septum fiber resulting in LTD in CA1.

The mechanism of long-term depression has been well characterized. However, how LTD affects motor learning and memory is still not well understood. Understanding this relationship is presently one of the major focuses of LTD research.