Myosin Va-dependent Transport of NMDA Receptors in Hippocampal Neurons.

N-methyl-D-aspartate receptor (NMDAR) trafficking is a key process in the regulation of synaptic efficacy and brain function. However, the molecular mechanism underlying the surface transport of NMDARs is largely unknown. Here we identified myosin Va (MyoVa) as the specific motor protein that traffics NMDARs in hippocampal neurons. We found that MyoVa associates with NMDARs through its cargo binding domain. This association was increased during NMDAR surface transport. Knockdown of MyoVa suppressed NMDAR transport. We further demonstrated that Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates NMDAR transport through its direct interaction with MyoVa. Furthermore, MyoVa employed Rab11 family-interacting protein 3 (Rab11/FIP3) as the adaptor proteins to couple themselves with NMDARs during their transport. Accordingly, the knockdown of FIP3 impairs hippocampal memory. Together, we conclude that in hippocampal neurons, MyoVa conducts active transport of NMDARs in a CaMKII-dependent manner.

Midbrain dopamine neurons arbiter OCD-like behavior.

The neurobiological understanding of obsessive-compulsive disorder (OCD) includes dysregulated frontostriatal circuitry and altered monoamine transmission. Repetitive stereotyped behavior (e.g., grooming), a featured symptom in OCD, has been proposed to be associated with perturbed dopamine (DA) signaling. However, the precise brain circuits participating in DA's control over this behavioral phenotype remain elusive. Here, we identified that DA neurons in substantia nigra pars compacta (SNc) orchestrate ventromedial striatum (VMS) microcircuits as well as lateral orbitofrontal cortex (lOFC) during self-grooming behavior. SNc-VMS and SNc-lOFC dopaminergic projections modulate grooming behaviors and striatal microcircuit function differentially. Specifically, the activity of the SNc-VMS pathway promotes grooming via D1 receptors, whereas the activity of the SNc-lOFC pathway suppresses grooming via D2 receptors. SNc DA neuron activity thus controls the OCD-like behaviors via both striatal and cortical projections as dual gating. These results support both pharmacological and brain-stimulation treatments for OCD.

Trafficking of NMDA receptors is essential for hippocampal synaptic plasticity and memory consolidation.

NMDA receptor (NMDAR) plays a vital role in brain development and normal physiological functions. Surface trafficking of NMDAR contributes to the modulation of synaptic functions and information processing. However, it remains unclear whether NMDAR trafficking is independent of long-term potentiation (LTP) and whether it regulates behavior. Here, we report that LTP of AMPAR and NMDAR can occur concurrently and that NMDAR trafficking can regulate AMPAR trafficking and AMPAR-mediated LTP. By contrast, AMPAR trafficking does not impact NMDAR-mediated LTP. Using SAP97-interfering peptide and SAP97 knockin (KI) rat, we show that the effect is mediated by GluN2A-subunit-containing NMDARs. At the behavior level, impaired NMDAR trafficking results in deficits in consolidation, but not acquisition, of fear memory. Collectively, our results suggest the essential role of NMDAR trafficking in LTP and memory consolidation.

NMDAR-dependent somatic potentiation of synaptic inputs is correlated with ß amyloid-mediated neuronal hyperactivity.

BACKGROUND: ß Amyloid (Aß)-mediated neuronal hyperactivity, a key feature of the early stage of Alzheimer's disease (AD), is recently proposed to be initiated by the suppression of glutamate reuptake. Nevertheless, the underlying mechanism by which the impaired glutamate reuptake causes neuronal hyperactivity remains unclear. Chronic suppression of the glutamate reuptake causes accumulation of ambient glutamate that could diffuse from synaptic sites at the dendrites to the soma to elevate the tonic activation of somatic N-methyl-D-aspartate receptors (NMDARs). However, less attention has been paid to the potential role of tonic activity change in extrasynaptic glutamate receptors (GluRs) located at the neuronal soma on generation of neuronal hyperactivity. METHODS: Whole-cell patch-clamp recordings were performed on CA1 pyramidal neurons in acute hippocampal slices exposed to TFB-threo-ß-benzyloxyaspartic acid (TBOA) or human Aß1-42 peptide oligomer. A series of dendritic patch-clamp recordings were made at different distances from the soma to identify the location of the changes in synaptic inputs. Moreover, single-channel recording in the cell-attached mode was performed to investigate the activity changes of single NMDARs at the soma. RESULTS: Blocking glutamate uptake with either TBOA or the human Aß1-42 peptide oligomer elicited potentiation of synaptic inputs in CA1 hippocampal neurons. Strikingly, this potentiation  specifically occurred at the soma, depending on the activation of somatic GluN2B-containing NMDARs (GluN2B-NMDARs) and accompanied by a substantial and persistent increment in the open probability of somatic NMDARs. Blocking the activity of GluN2B-NMDARs at the soma completely reversed both the TBOA-induced or the Aß1-42-induced somatic potentiation and neuronal hyperactivity. CONCLUSIONS: The somatic potentiation of synaptic inputs may represent a novel amplification mechanism that elevates cell excitability and thus contributes to neuronal hyperactivity initiated by impaired glutamate reuptake in AD.

Long-Lasting Somatic Modifications of Convergent Dendritic Inputs in Hippocampal Neurons.

Integrated neural inputs from different dendrites converge at the soma for action potential generation. However, it is unclear how the convergent dendritic inputs interact at the soma and whether they can be further modified there. We report here an entirely new plasticity rule in hippocampal neurons in which repetitive pairing of subthreshold excitatory inputs from proximal apical and basal dendrites at a precise interval induces persistent bidirectional modifications of the two dendritic inputs. Strikingly, the modification of the dendritic inputs specially occurs at soma in the absence of somatic action potential and requires activation of somatic N-methyl-D-aspartate receptors (NMDARs). Once induced, the somatic modification can also be observed in other unpaired dendritic inputs upon their arrival at the soma. We further reveal that the soma can employ an active mechanism to potentiate the dendritic inputs by promoting sustained activation of somatic NMDARs and subsequent down-regulating of the fast inactivating A-type potassium current (IA) at the soma. Thus, the input-timing-dependent somatic plasticity we uncovered here is in sharp contrast to conventional forms of synaptic plasticity that occur at the dendrites and is important to somatic action potential generation.

Werner complex deficiency in cells disrupts the Nuclear Pore Complex and the distribution of lamin B1.

From the surrounding shell to the inner machinery, nuclear proteins provide the functional plasticity of the nucleus. This study highlights the nuclear association of Pore membrane (POM) protein NDC1 and Werner protein (WRN), a RecQ helicase responsible for the DNA instability progeria disorder, Werner Syndrome. In our previous publication, we connected the DNA damage sensor Werner's Helicase Interacting Protein (WHIP), a binding partner of WRN, to the NPC. Here, we confirm the association of the WRN/WHIP complex and NDC1. In established WRN/WHIP knockout cell lines, we further demonstrate the interdependence of WRN/WHIP and Nucleoporins (Nups). These changes do not completely abrogate the barrier of the Nuclear Envelope (NE) but do affect the distribution of FG Nups and the RAN gradient, which are necessary for nuclear transport. Evidence from WRN/WHIP knockout cell lines demonstrates changes in the processing and nucleolar localization of lamin B1. The appearance of "RAN holes" void of RAN corresponds to regions within the nucleolus filled with condensed pools of lamin B1. From WRN/WHIP knockout cell line extracts, we found three forms of lamin B1 that correspond to mature holoprotein and two potential post-translationally modified forms of the protein. Upon treatment with topoisomerase inhibitors lamin B1 cleavage occurs only in WRN/WHIP knockout cells. Our data suggest the link of the NDC1 and WRN as one facet of the network between the nuclear periphery and genome stability. Loss of WRN complex leads to multiple alterations at the NPC and the nucleolus.