Eun-Jae Lee

NMDA receptor dysfunction in autism spectrum disorders

Abnormalities and imbalances in neuronal excitatory and inhibitory synapses have been implicated in diverse neuropsychiatric disorders including autism spectrum disorders (ASDs). Increasing evidence indicates that dysfunction of NMDA receptors (NMDARs) at excitatory synapses is associated with ASDs. In support of this, human ASD-associated genetic variations are found in genes encoding NMDAR subunits. Pharmacological enhancement or suppression of NMDAR function ameliorates ASD symptoms in humans. Animal models of ASD display bidirectional NMDAR dysfunction, and correcting this deficit rescues ASD-like behaviors. These findings suggest that deviation of NMDAR function in either direction contributes to the development of ASDs, and that correcting NMDAR dysfunction has therapeutic potential for ASDs.

Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activation

Genetic aspects of autism spectrum disorders (ASDs) have recently been extensively explored, but environmental influences that affect ASDs have received considerably less attention. Zinc (Zn) is a nutritional factor implicated in ASDs, but evidence for a strong association and linking mechanism is largely lacking. Here we report that trans-synaptic Zn mobilization rapidly rescues social interaction in two independent mouse models of ASD. In mice lacking Shank2, an excitatory postsynaptic scaffolding protein, postsynaptic Zn elevation induced by clioquinol (a Zn chelator and ionophore) improves social interaction. Postsynaptic Zn is mainly derived from presynaptic pools and activates NMDA receptors (NMDARs) through postsynaptic activation of the tyrosine kinase Src. Clioquinol also improves social interaction in mice haploinsufficient for the transcription factor Tbr1, which accompanies NMDAR activation in the amygdala. These results suggest that trans-synaptic Zn mobilization induced by clioquinol rescues social deficits in mouse models of ASD through postsynaptic Src and NMDAR activation.

Splicing-Dependent Trans-synaptic SALM3–LAR-RPTP Interactions Regulate Excitatory Synapse Development and Locomotion

SUMMARY Synaptic adhesion molecules regulate diverse aspects of synapse development and plasticity. SALM3 is a PSD-95-interacting synaptic adhesion molecule known to induce presynaptic differentiation in contacting axons, but little is known about its presynaptic receptors and in vivo functions. Here, we identify an interaction between SALM3 and LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) that requires the mini-exon B splice insert in LAR-RPTPs. In addition, SALM3-dependent presynaptic differentiation requires all three types of LAR-RPTPs. SALM3 mutant (Salm3−/−) mice display markedly reduced excitatory synapse number but normal synaptic plasticity in the hippocampal CA1 region. Salm3−/− mice exhibit hypoactivity in both novel and familiar environments but perform normally in learning and memory tests administered. These results suggest that SALM3 regulates excitatory synapse development and locomotion behavior.

Long-term depression-inducing stimuli promote cleavage of the synaptic adhesion molecule NGL-3 through NMDA receptors, matrix metalloproteinases and presenilin/γ-secretase

Long-term depression (LTD) reduces the functional strength of excitatory synapses through mechanisms that include the removal of AMPA glutamate receptors from the postsynaptic membrane. LTD induction is also known to result in structural changes at excitatory synapses, including the shrinkage of dendritic spines. Synaptic adhesion molecules are thought to contribute to the development, function and plasticity of neuronal synapses largely through their trans-synaptic adhesions. However, little is known about how synaptic adhesion molecules are altered during LTD. We report here that NGL-3 (netrin-G ligand-3), a postsynaptic adhesion molecule that trans-synaptically interacts with the LAR family of receptor tyrosine phosphatases and intracellularly with the postsynaptic scaffolding protein PSD-95, undergoes a proteolytic cleavage process. NGL-3 cleavage is induced by NMDA treatment in cultured neurons and low-frequency stimulation in brain slices and requires the activities of NMDA glutamate receptors, matrix metalloproteinases (MMPs) and presenilin/γ-secretase. These results suggest that NGL-3 is a novel substrate of MMPs and γ-secretase and that NGL-3 cleavage may regulate synaptic adhesion during LTD.

String tyre model for evaluating steering agility performance using tyre cornering force and lateral static characteristics

ABSTRACT The cornering force and lateral static characteristics of a tyre are fundamental factors that describe the steering feel for handling performance. However, it is difficult to justify the contribution of each factor when the tyre’s cornering motion is evaluated through subjective assessment. Currently, the relaxation length of Pacejka’s tyre model is close to describing these tyre motions. Therefore, this paper proposes a string tyre model based on the relaxation length in order to represent the steering performance. The proposed method provides a more accurate modelling of the steering agility performance. Therefore, it is possible to use this model to predict the steering response performance, and this is validated through comparison with a real relaxation length.

Early detection of tire-road friction coefficient based on pneumatic trail stiffness

This paper presents a method for estimating the maximum lateral tire-road friction coefficient and wheel side slip angle based on the pneumatic trail information that exhibits unique characteristics according to the road surface conditions. The high sensitivity of the pneumatic trail for the wheel side slip angle enables the proposed observer to detect the peak tire-road friction coefficient in low slip regions. The conventional method that is highly dependent on the tire model has drawbacks due to model uncertainty. In order to overcome these shortcomings, the proposed method minimizes the use of existing tire models. In addition, traction force is also considered in this paper using a correction factor. The estimation results are obtained recursively under the persistent excitation condition. A simulation is conducted first in order to verify the performance of the proposed method using a combination of the Carsim and Matlab & Simulink. Then, vehicle experiments are conducted on a proving ground in order to verify the feasibility of the proposed method. The verification results reveal that the early detection of the maximum tire-road friction coefficient is possible with less excitation signals than the conventional methods.

Estimation of the maximum lateral tire-road friction coefficient using the 6-DoF sensor

Estimated peak tire-road friction coefficient can be implemented on various vehicle active safety control systems. But, it is not easy to get the actual data from the road cause of cost, equipment installation, maintenance and technical issues. The demands for real-time estimation of peak friction coefficient have been increased due to the above mentioned technical shortcomings. This paper provides the lateral tire-road friction coefficient estimation method using a simplified Dugoff tire model under the pure side slip condition. The rearranged Dugoff model respect to lateral friction coefficient consists of lateral tire force, normal tire force, wheel side slip angle and cornering stiffness. Therefore, aforementioned parameters are also identified based on vehicle model or it is assumed to be constant values in the proposed algorithm. The performance of developed algorithm is verified by Carsim and Matlab/Simulink. The simulation results encourage possible development of the proposed method in this paper.