Long-term depression
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.
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.
[5] 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.
To prevent neurons from becoming static, there are two regulatory forms of plasticity that provide negative feedback: metaplasticity and scaling.
The weakening of a synapse is independent of the activity of the presynaptic or postsynaptic neurons as a result of the firing of a distinct modulatory interneuron.
[12] 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).
Selective activation of these phosphatases by varying calcium levels might be responsible for the different effects of calcium observed during LTD.[2] 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.
Glutamate binding to the metabotropic receptor activates phospholipase C (PLC) and produces diacylglycerol (DAG) and inositol triphosphate (IP3) second messengers.
PKC phosphorylates AMPA receptors, which promotes their dissociation from scaffold proteins in the post-synaptic membrane and subsequent internalization.
With the loss of AMPA receptors, the postsynaptic Purkinje cell response to glutamate release from parallel fibers is depressed.
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.
There is a positive feedback loop that results from a simultaneous input of signals from PF-CF and increases DAG and Ca2+ in Purkinje dendritic spines.
[1] The second is initiated by a high frequency stimulus and is arbitrated by presynaptic mGlu receptor 2 or 3, resulting in a long term reduction in the involvement of P/Q-type calcium channels in glutamate release.
[1] The third form of LTD requires endocannabinoids, activation of mGlu receptors and repetitive stimulation of glutamatergic fibers (13 Hz for ten minutes), resulting in a long-term decrease in presynaptic glutamate release.
[1] It is proposed that LTD in GABAergic striatal neurons leads to a long-term decrease in inhibitory effects on the basal ganglia, influencing the storage of motor skills.
[20] This type of LTD is similar to that found in the hippocampus, because it is triggered by a small elevation in postsynaptic calcium ions and activation of phosphatases.
[1] It has been found that paired-pulse stimulation (PPS) induces a form of homosynaptic LTD in the superficial layers of the visual cortex when the synapse is exposed to carbachol (CCh) and norepinephrine (NE).
This mechanism possibly underlies serotonin's role in the control of cognitive and emotional processes that synaptic plasticity in PFC neurons mediates.
[24] 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.
They are involved in inhibition of LTD at parallel fiber Purkinje neuron synapses in the cerebellum and NMDA receptor-dependent LTD in the hippocampus.
[30] Previous research has strictly focused on the aspects of neuronal LTD, however, emerging studies have shown astrocyte contribution to LTD in tripartite synapses.
Some forms of STDP that occur with NMDA receptors and mGluRs have shown that astrocyte cooperation is necessary, especially on the synapses of parallel fibers onto Purkinje cells.
In one study, metabotropic glutamate receptor 1 mutant mice maintained a normal cerebellar anatomy but had weak LTD and consequently impaired motor learning.
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).
[40] Studies show that NMDA receptors role in learning can be hindered by alcohol in three major regions: dorsal striatum, neocortex, and hippocampus.
[41] In particular, these studies show that LTD due to alcohol is found in the dorsal striatum and the hippocampus, with deficits in the neocortex being caused by white and grey-matter degradation.
Although LTD in the dorsal striatum was found when exposed to high frequency stimulation, a simulation of alcohol tolerance and withdrawal resulted in LTP in the same region.
Specifically, LTD was found after activation of NMDA receptors in the CA1 region of the hippocampus, with evidence that an inhibition of glutamatergic interactions cause the hippocampal deficits.
[42] 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.
Anti-VGCC, anti-mGluR1, and anti-GluR delta Abs-associated cerebellar ataxias share one common pathophysiological mechanism: a deregulation in PF-PC LTD.
