Loss of a Scaffold Protein Leads to Excessive GTPase Activity
Taira Mayanagi, Hiroki Yasuda, and Kenji Sobue
(see pages 14327–14340)
The strength of glutamatergic synapses is determined largely by the number of AMPA receptors in the postsynaptic density and the size and shape of dendritic spines. These characteristics are regulated partly by the small GTPases Ras, Rap1, and Rap2. Specifically, Ras promotes AMPA receptor insertion and maturation of spines from thin to mushroom-shaped, whereas Rap1/2 promotes AMPA receptor removal and spine loss. The activity of small GTPases is enhanced by guanine nucleotide exchange factors (GEFs) and inhibited (counterintuitively) by GTPase activating proteins (GAPs). To function efficiently, all these proteins—along with innumerable other proteins involved in synaptic communication—must be kept well organized in dendritic spines. This is accomplished by scaffolding proteins.
Knocking out PSD-Zip70 (right) reduced surface expression of GluR2 (top), but not total expression of GluR2/3 (bottom). See Mayanagi et al. for details.
The importance of scaffolding proteins in synaptic function is illustrated by Mayanagi et al., who studied the forebrain-enriched protein PSD-Zip70. Previous studies showed that PSD-Zip70 binds SPAR, a Rap GAP enriched in spines. Mayanagi et al. found that PSD-Zip70 also interacts with the Rap GEFs PDZ-GEF1 and PDZ-GEF2 and colocalizes with Rap2 in dendritic spines in prefrontal cortex. Knocking out PSD-Zip70 caused SPAR to diffuse along dendritic shafts, resulting in increased Rap2 activity. This was accompanied by an increase in thin (immature) spines and a decrease in mushroom-shaped (mature) spines. Additionally, surface expression of AMPA receptor subunits GluR1 and GluR2/3 was reduced, while expression of NMDA receptor subunit NR2B was increased in PSD-Zip70-deficient neurons. Finally, PSD-Zip70-deficient mice exhibited behavioral abnormalities in elevated-plus and Y mazes.
The effects of PSD-Zip70 knockout on spine morphology were mimicked in wild-type neurons by overexpressing PDZ-GEF1, PDZ-GEF2, an inactive form of SPAR, or a constitutively active form of Rap2. Furthermore, the effects were rescued by overexpressing SPAR or knocking down Rap2 or PDZ-GEF1 and PDZ-GEF2. Finally, expressing dominant-negative Rap2 in the mPFC rescued behavioral abnormalities in PSD-Zip70-deficient mice.
These results suggest that loss of PSD-Zip70 disrupts SPAR-dependent inhibition of Rap2, and that the resulting increase in Rap2 activity reduces surface expression of AMPA receptors and impedes spine maturation. Because PSD-Zip70 is encoded by a chromosomal region that contains mutations linked to schizophrenia and autism, the results indicate a possible role for PSD-Zip70 in these conditions.
Passive Movement Drives Motor Skill Acquisition
Nicolò F. Bernardi, Mohammad Darainy, and David J. Ostry
(see pages 14316–14326)
When the motor cortex commands a movement, the resulting muscle contractions provide somatosensory feedback that indicates whether the intended movement was produced. If a mismatch occurs, the command is modified to reduce error. But when commanding a new behavior, the brain often doesn't know what the intended movement should be, so somatosensory error signals may not be useful for determining whether the command should be modified. Does somatosensory information still play a role in shaping motor learning in such cases?
To address this question, Bernardi et al. investigated whether passive movements that replicate the kinematics produced during active movement are able to refine motor skill. Subjects were first tested for their ability to make a precise movement straight ahead or at a 135° angle, as well as on their ability to determine the angle at which their arms were moved by a robot. During subsequent training, one group of subjects was instructed to move a robotic arm precisely straight ahead or at 135°. All the trajectories used by these subjects—whether accurate or not—were then used to passively move the arms of a group of yoked subjects who were told to focus on how the movement felt. Neither group of subjects could see their arms or the target during trials, but both groups were told when the movement was accurate. Afterwards, both groups were again tested on their accuracy in making the trained arm movement and on their ability to estimate the angle at which a robot moved their arms. The two groups showed similar improvements on both tests, and for both groups, improvements were retained for at least a week. Importantly, the improvement was not simply attributable to subjects learning the precise spatial location of the target, because the performance of control participants did not improve when they were only shown the end point of each trajectory performed by an active-group subject.
These results clearly indicate that learning what a desired action feels like has an essential role in the early stages of motor learning. An important question for future studies is whether passive training exclusively with accurate trajectories can speed or enhance the acquisition of precise motor skills.
