Important Role In Motor Learning Research Articles

Binding of glutamate receptor δ2 to its scaffold protein, Delphilin, is regulated by PKA

The glutamate receptor δ2 (GluRδ2) is selectively expressed in cerebellar Purkinje cells and plays an important role in motor learning, motor coordination, and long-term depression. Delphilin is identified as a GluRδ2-interacting protein, selectively expressed in Purkinje cell-parallel fiber synapses, and specifically interacts with the GluRδ2 C-terminus via its PDZ domain. Here, surface plasmon resonance analyses showed that Delphilin PDZ bound to GluRδ2 C-terminal peptide (DPDRGTSI), but not to its phosphopeptides (DPDRGphosphoTSI and DPDRGTphosphoSI). We showed the incorporation of phosphate into threonine at −2 (−2T) and serine at −1 (−1S) of GluRδ2 C-terminus by cAMP-dependent protein kinase (PKA) in vitro. In the experiments using heterologous expression system, Delphilin coimmunoprecipitated with GluRδ2 was dramatically decreased under the condition with forskolin and isobutylmethylxanthine, which led to cAMP-dependent phosphorylation by PKA. Thus, phosphorylation of −2T and/or −1S of GluRδ2 C-terminus by PKA may regulate the binding of GluRδ2 to its scaffolding protein, Delphilin.

Plasminogen activators and synaptic plasticity

In addition to its role in the vascular system, plasminogen activator (PA) is involved in neural development, excitotoxic cell death, and has been implicated in aspects of cerebral synaptic remodeling associated with cerebellar motor learning, visual cortex ocular dominance columns, and hippocampal & corticostriatal LTP. During a complex motor task cerebellar granule neurons show a rapid and transient induction of mRNA for the extracellular protease tissue plasminogen activator (tPA). This induction of tPA is cerebellar specific, and is not seen in the cerebella of exercised or stressed mice, and is distinct from simple performance phenomena. Knock-out mice lacking the tPA gene show a significant reduction in both rate and extent of learning the complex motor task. Furthermore, blocking tPA activity by infusion of PAI-1 or tPA-STOP during training dramatically impairs motor learning. Thus, tPA plays and important role in motor learning, in which tPA may facilitate synaptic plasticity. We have explored the possibility that PA may also play a role in synaptic plasticity in the spinal cord. The crossed phrenic phenomenon (CPP) describes respiratory functional plasticity that arises following spinal cord injury; whereby, phrenic motoneuron drive to the diaphragm is restored following activation of functionally ineffective medullary respiratory neuron synapses on phrenic motoneurons (PMN). Synaptic remodeling is thought to occur during the characteristic delay period following spinal cord injury before the CPP becomes functional. The mechanisms underlying this synaptic plasticity are not well-defined. Our ultimate aim is to understand the underlying molecular mechanisms of this functional recovery using a mouse model amenable to a molecular genetic approach, and ours is the first report of CPP in mice. Using electromyographic (EMG) recordings from the diaphragm, we examined the inter-operative delay time between spinal cord hemisection and contralateral phrenicotomy required for diaphragm response, as compared to animal death from asphyxia at zerotime. For each animal, a spinal cord hemisection was performed on the left side at C2. A contralateral phrenicotomy was performed the next day (overnight animals), 6–8 hours, 4–5 hours, or 1–2 hours post-hemisection. As the inter-operative delay was reduced, the proportion of mice displaying the CPP decreased from 100% for overnight animals, 94% in 6–8 h, 82% in 4–5 h, to 76% for 1–2 h mice. A critical 1–2 hr window is required for this synaptic plasticity. In situ hybridization shows that uPA and tPA mRNAs are rapidly induced in C4-5 ventral spinal cord neurons in the ipsilateral phrenic nucleus compared to the contralateral PMN and sham controls, with markedly elevated tPA protein at 1hr. post-hemisection. This specific and concomitant induction of PA suggests a role in CPP spinal cord plasticity, which may ultimately lead to therapeutic uses for PA in spinal cord injury.

Absence of Tissue Plasminogen Activator Gene or Activity Impairs Mouse Cerebellar Motor Learning

Motor learning is thought to involve modulation of synaptic inputs in the cerebellar cortex, including granule neuron/Purkinje neuron contacts. During a complex motor task requiring mice to walk across irregularly spaced pegs, cerebellar granule neurons show a rapid and transient induction of mRNA for the extracellular protease tissue plasminogen activator (tPA). This induction of tPA mRNA is cerebellar specific, is not seen in the cerebella of exercised or stressed animals, and is distinct from simple performance phenomena. Knock-out mice lacking the tPA gene show a significant reduction in both rate and extent of learning. Furthermore, blocking tPA activity during training dramatically impaired motor learning. Thus, tPA plays an important role in motor learning, in which tPA may facilitate remodeling of the active synaptic zone.

Reacquisition deficits in prism adaptation after muscimol microinjection into the ventral premotor cortex of monkeys.

A small amount of muscimol (1 microl; concentration, 5 microg/microl) was injected into the ventral and dorsal premotor cortex areas (PMv and PMd, respectively) of monkeys, which then were required to perform a visually guided reaching task. For the task, the monkeys were required to reach for a target soon after it was presented on a screen. While performing the task, the monkeys' eyes were covered with left 10 degrees, right 10 degrees, or no wedge prisms, for a block of 50-100 trials. Without the prisms, the monkeys reached the targets accurately. When the prisms were placed, the monkeys initially misreached the targets because the prisms displaced the visual field. Before the muscimol injection, the monkeys adapted to the prisms in 10-20 trials, judging from the horizontal distance between the target location and the point where the monkey touched the screen. After muscimol injection into the PMv, the monkeys lost the ability to readapt and touched the screen closer to the location of the targets as seen through the prisms. This deficit was observed at selective target locations, only when the targets were shifted contralaterally to the injected hemisphere. When muscimol was injected into the PMd, no such deficits were observed. There were no changes in the reaction and movement times induced by muscimol injections in either area. The results suggest that the PMv plays an important role in motor learning, specifically in recalibrating visual and motor coordinates.

Does the cerebellum learn strategies for the optimal time-varying control of joint stiffness?

Although there is increasing agreement that the cerebellum plays an important role in motor learning, the basic substance of what constitutes motor learning has been difficult to define. Unless motor learning is somehow radically different from other forms of learning, it must involve relatively simple stimulus-stimulus and stimulus-response associations. All forms of learning, including purely sensory associations and cognitive learning as well as motor learning, effect changes in behavior. However, a singular characteristic of motor learning is that it adjusts joint and limb mechanics by altering the neural input to muscles through practice and mental rehearsal. The hypothesis proposed here is that the cerebellum plays an important role in motor learning by forming and storing associated muscle activation patterns for the time-varying control of limb mechanics. By modulating the cocontraction of agonist-antagonist muscles through adjustments in the timing and amplitude of muscle activity, the viscoelastic properties of joints can be appropriately regulated throughout Movement and adapted for transitions between postures and movements. Optimal control of joint viscoelastic properties cannot be achieved by online corrections initiated by reflex feedback because of the delays and consequent instabilities incurred. Instead, strategies for optimizing muscle activation patterns or synergies must be learned from the temporal association of proprioceptive stimuli signaling muscle lengths and forces and the rates of changes in these parameters, with reinforcement occurring when the movement achieves its objective. Such strategies would involve varying degrees of cocontraction or reciprocal inhibition of agonist-antagonist muscles that ultimately contribute to joint and limb stiffness. Evidence from neural recordings and clinical and experimental lesion studies are presented, suggesting that the cerebellum uses teleceptive and proprioceptive feedback as feedforward conditioned stimuli for specific muscle activation patterns contributing to joint stiffness (i.e., agonist-antagonist muscle synergies) for particular tasks and postures. A wide variety of observations are thought to be consistent with such a role for the cerebellum, but ultimately additional experiments could confirm or disconfirm this hypothesis.

Long-lasting potentiation of GABAergic inhibitory synaptic transmission in cerebellar Purkinje cells: Its properties and possible mechanisms

The cellular basis of motor learning in the cerebellum has been attributed mostly to long-term depression (LTD) at excitatory parallel fiber (PF)-Purkinje cell (PC) synapses. LTD is induced when PFs are activated in conjunction with a climbing fiber (CF), the other excitatory input to PCs. Recently, by using whole-cell patch-clamp recording from PCs in cerebellar slices, a new form of synaptic plasticity was discovered. Stimulation of excitatory CFs induced a long-lasting (usually longer than 30 min) “rebound potentiation (RP)” of γ-amino-butyric acid A (GABAa)-receptor mediated inhibitory postsynaptic, currents (IPSCs). As in LTD, induction of RP requires transient elevation of intracellular calcium concentration ([Ca2+]1) due to activation of voltage-gated Ca2+ channels. Activity of inhibitory synapses seems also to be necessary for RP to occur. RP is mainly due to up-regulation of postsynaptic GABAa receptor function, since PC response to bath-applied exogenous GABA is also potentiated with a time course similar to RP. The difference in the time scale between the Ca2+ transients (10–30 sec) and the durations of RP (>30 min) strongly suggests that some intracellular biochemical machinery is involved. Pharmacological evidence suggests that protein kinases are involved in RP of inhibitory synapses and LTD of excitatory PF synapses. Besides the well-described LTD, RP could be a cellular mechanism that plays an important role in motor learning.

Error detection and correction in a structured movement task.

Error-detection and error-correction experiments were conducted to examine the assumption that organizational processes play an important role in motor learning and control. During the initial phase of each experiment, the sensory aspects of five movements were held constant while the organizational structure (sequential vs. random) of the movements was varied. In the learning phase of both experiments, the effect of organization produced increased reproduction accuracy for the structured movement sequences compared to those that were random. This benefit of organization carried over into the error detection and correction parts of the experiments where it was shown that improved error detection and correction capabilities were assisted by the manner in which the movements were presented. The importance of cognitive processes is discussed in terms of past and contemporary accounts of motor learning and control.