The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit-and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory-inhibitory balance.leucine-rich repeat | neuropsychiatic disorder | synaptic cell-adhesion

Current selection criteria of liver transplantation (LT) for patients with hepatocellular carcinoma (HCC) were derived from the outcomes of cadaveric donor LT (CDLT). We tried to assess the applicability of such criteria to living donor LT (LDLT) through a comparative study between CDLT and LDLT. We analyzed the outcomes of 312 HCC patients who underwent LT at 4 Korean institutions during 1992 to 2002. There were no gross differences of tumor characteristics between CDLT group (n ‫؍‬ 75) and LDLT group (n ‫؍‬ 237). Overall 3-year survival rate (3-YSR) was 61.1% after CDLT and 73.2% after LDLT including 38 cases of perioperative mortality. Comparison of HCC recurrence curves did not reveal any statistical difference between these 2 groups. Patient survival period till 50% mortality after HCC recurrence was 11 months after CDLT and 7 months after LDLT. Significant risk factors for HCC recurrence were alpha-fetoprotein level, tumor size, microvascular invasion, gross major vessel invasion, bilateral tumor distribution, and histologic differentiation in the LDLT group on univariate analysis, and tumor size, gross major vessel invasion, and histologic differentiation on multivariate analysis. Milan criteria were met in 70.4%: Their 3-YSR was 89.9% after CDLT and 91.4% after LDLT with exclusion of perioperative mortality. University of California San Francisco criteria were met in 77.7%: Their 3-YSR was 88.1% after CDLT and 90.6% after LDLT. In conclusion, we think that currently available selection criteria for HCC patients can be applicable to LDLT without change of prognostic power. (Liver Transpl 2005;11: 1265-1272.)C onventional standard treatments of hepatocellular carcinoma (HCC) include surgical resection and nonsurgical treatments such as chemoembolization, ablation, and injection therapy. 1 However, surgical resection has a definite limitation in both tumor resectability and patient safety if hepatic functional reserve is markedly impaired. Nonsurgical treatments often resulted in incomplete tumor control and also revealed high recurrence rate when they were applied to the advanced HCC lesions. On the other hand, liver transplantation (LT) offers a chance to eliminate both tumor and underlying liver cirrhosis at the same time, although there is an additional risk of accelerated tumor recurrence from immunosuppression. If an HCC lesion is not too far advanced such as to meet the Milan criteria, a satisfactory outcome of LT will be statistically achievable. [2][3][4] From the viewpoints of quality of life and tumor recurrence, any other treatment modalities cannot achieve such a favorable result comparable to that of LT.The Milan criteria have been standard eligibility criteria of LT for HCC, but the indication of HCC patients has been prudently expanded in some major LT centers, and their outcomes were also comparably favorable like those within the Milan criteria. 5,6 We feel that there is a trend toward expanding the selection criteria of LT for HCC beyond the Milan criteria. 7 At this point, it should be c...

Periventricular leucomalacia has long been investigated as a leading cause of motor and cognitive dysfunction in patients with spastic diplegic cerebral palsy. However, patients with periventricular leucomalacia on conventional magnetic resonance imaging do not always have motor dysfunction and preterm children without neurological abnormalities may have periventricular leucomalacia. In addition, it is uncertain whether descending motor tract or overlying cortical injury is related to motor impairment. To investigate the relationship between motor pathway injury and motor impairment, we conducted voxelwise correlation analysis using tract-based spatial statistics of white matter diffusion anisotropy and voxel-based-morphometry of grey matter injury in patients with periventricular leucomalacia and spastic diplegia (n = 43, mean 12.86 ± 4.79 years, median 12 years). We also evaluated motor cortical and thalamocortical connectivity at resting state in 11 patients using functional magnetic resonance imaging. The functional connectivity results of patients with spastic diplegic cerebral palsy were compared with those of age-matched normal controls. Since γ-aminobutyric acid(A) receptors play an important role in the remodelling process, we measured neuronal γ-aminobutyric acid(A) receptor binding potential with dynamic positron emission tomography scans (n = 27) and compared the binding potential map of the patient group with controls (n = 20). In the current study, white matter volume reduction did not show significant correlation with motor dysfunction. Although fractional anisotropy within most of the major white matter tracts were significantly lower than that of age-matched healthy controls (P < 0.05, family wise error corrected), fractional anisotropy mainly within the bilateral corticospinal tracts and posterior body and isthmus of the corpus callosum showed more significant correlation with motor dysfunction (P < 0.03) than thalamocortical pathways (P < 0.05, family-wise error corrected). Cortical volume of the pre- and post-central gyri and the paracentral lobule tended to be negatively correlated with motor function. The motor cortical connectivity was diminished mainly within the bilateral somatosensory cortex, paracentral lobule, cingulate motor area and visual cortex in the patient group. Thalamovisual connectivity was not diminished despite severe optic radiation injury. γ-Aminobutyric acid(A) receptor binding potential was focally increased within the lower extremity homunculus, cingulate cortex, visual cortex and cerebellum in the patient group (P < 0.05, false discovery rate corrected). In conclusion, descending motor tract injury along with overlying cortical volume reduction and reduced functional connectivity appears to be a leading pathophysiological mechanism of motor dysfunction in patients with periventricular leucomalacia. Increased regional γ-aminobutyric acid(A) receptor binding potential appears to result from a compensatory plasticity response after prenatal brain injury.

Metabotropic glutamate receptors (mGluRs) 1-8 are G proteincoupled receptors (GPCRs) that modulate excitatory neurotransmission, neurotransmitter release, and synaptic plasticity. PKC regulates many aspects of mGluR function, including protein-protein interactions, Ca 2؉ signaling, and receptor desensitization. However, the mechanisms by which PKC regulates mGluR function are poorly understood. We have now identified calmodulin (CaM) as a dynamic regulator of mGluR5 trafficking. We show that the major PKC phosphorylation site on the intracellular C terminus of mGluR5 is serine 901 (S901), and phosphorylation of this residue is up-regulated in response to both receptor and PKC activation. In addition, S901 phosphorylation inhibits mGluR5 binding to CaM, decreasing mGluR5 surface expression. Furthermore, blocking PKC phosphorylation of mGluR5 on S901 dramatically affects mGluR5 signaling by prolonging Ca 2؉ oscillations. Thus, our data demonstrate that mGluR5 activation triggers phosphorylation of S901, thereby directly linking PKC phosphorylation, CaM binding, receptor trafficking, and downstream signaling.phosphorylation ͉ protein kinase C ͉ receptor trafficking T he group I metabotropic glutamate receptor mGluR5 is highly expressed in the forebrain, where it regulates synaptic plasticity (1, 2). In addition, mGluR5 plays a role in pain (3) and addiction (4) and in neurological disorders such as fragile X syndrome (5, 6). Group I mGluRs are G protein-coupled receptors (GPCRs), which are coupled to phospholipase C, and receptor activation triggers phosphoinositide turnover, release of intracellular Ca 2ϩ , and activation of Protein Kinase C (PKC) (7). Although PKC activity regulates mGluR5-mediated Ca 2ϩ signaling and receptor function (8-11), there are no studies linking PKC phosphorylation of mGluR5 to receptor surface expression, endocytosis, or intracellular trafficking.Like other GPCRs, mGluR5 interacts with many proteins in addition to the guanine nucleotide-binding proteins (G proteins). Most of the binding sites for these protein-protein interactions reside within the long intracellular C-terminal domain of mGluR5, suggesting that this region is critical in the functional regulation of mGluR5. For example, the Homer proteins bind to the PPxxFR motif within the distal C terminus, the Tamalin protein associates with the distal C terminus, and calmodulin (CaM) and the E3 ligase Siah-1A bind to the first one-third of the mGluR5 C terminus (12-15). However, the dynamic regulation of these protein-protein interactions has not been described. CaM is a particularly intriguing candidate as an mGluR5 regulator because of its Ca 2ϩ dependence and its key role in synaptic plasticity (16,17). Furthermore, CaM binding to other GPCRs, including dopamine, opioid, and serotonin receptors, has been documented, consistent with a conserved regulatory role for CaM in regulating . We now show that PKC phosphorylation of serine 901 (S901) on mGluR5 inhibits CaM binding and decreases mGluR5 surface expression. Furthermore, preve...