PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton, modulating emotional behavior.

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function. Synaptic abnormalities, such as defects in the density and morphology of postsynaptic dendritic spines, underlie the pathology of various neuropsychiatric disorders. Protocadherin 17 (PCDH17) is associated with major mood disorders, including bipolar disorder and depression. However, the molecular mechanisms by which PCDH17 regulates spine number, morphology, and behavior remain elusive. In this study, we found that PCDH17 functions at postsynaptic sites, restricting the number and size of dendritic spines in excitatory neurons. Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety- and depression-like behaviors in mice. Mechanistically, PCDH17 interacts with actin-relevant proteins and regulates actin filament (F-actin) organization. Specifically, PCDH17 binds to ROCK2, increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3 (Ser3). Inhibition of ROCK2 activity with belumosudil (KD025) ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression, suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development. Hence, these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior, providing pathological insights into the neurobiological basis of mood disorders.

Synaptic plasticity in schizophrenia pathophysiology.

Schizophrenia is a severe neuropsychiatric syndrome with psychotic behavioral abnormalities and marked cognitive deficits. It is widely accepted that genetic and environmental factors contribute to the onset of schizophrenia. However, the etiology and pathology of the disease remain largely unexplored. Recently, the synaptopathology and the dysregulated synaptic plasticity and function have emerging as intriguing and prominent biological mechanisms of schizophrenia pathogenesis. Synaptic plasticity is the ability of neurons to change the strength of their connections in response to internal or external stimuli, which is essential for brain development and function, learning and memory, and vast majority of behavior responses relevant to psychiatric diseases including schizophrenia. Here, we reviewed molecular and cellular mechanisms of the multiple forms synaptic plasticity, and the functional regulations of schizophrenia-risk factors including disease susceptible genes and environmental alterations on synaptic plasticity and animal behavior. Recent genome-wide association studies have provided fruitful findings of hundreds of risk gene variances associated with schizophrenia, thus further clarifying the role of these disease-risk genes in synaptic transmission and plasticity will be beneficial to advance our understanding of schizophrenia pathology, as well as the molecular mechanism of synaptic plasticity.

Association of variants in the KIF1A gene with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in many other neurodegenerative disorders, the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport. Notably, sensory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2 (HSAN2) and spastic paraplegia 30 (SPG30) share several causative genes with ALS, as well as having common clinical phenotypes. KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors (SVPs) and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30. METHODS: Here, we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS. RESULTS: We identified rare damage variants (RDVs) in the KIF1A gene associated with ALS and delineated the clinical characteristics of ALS patients with KIF1A RDVs. Clinically, these patients tended to exhibit sensory disturbance. Interestingly, the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein. Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A, VAMP2, and synaptophysin. Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor. CONCLUSIONS: Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS, indicating KIF1A as an important player in the oligogenic scenario of ALS.

PINK1-mediated Drp1S616 phosphorylation modulates synaptic development and plasticity via promoting mitochondrial fission.

Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here that Pink1 knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation in Pink1 KO neurons. Notably, mice harboring a knockin (KI) phosphor-null Drp1S616A recapitulate spine immaturity and synaptic abnormality identified in Pink1 KO mice. Chemical LTP (cLTP) induces Drp1S616 phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1S616D restores reduced dendritic spine localization of mitochondria in Pink1 KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1S616 phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement.

Synaptic plasticity in schizophrenia pathophysiology.

Schizophrenia is a severe neuropsychiatric syndrome with psychotic behavioral abnormalities and marked cognitive deficits. It is widely accepted that genetic and environmental factors contribute to the onset of schizophrenia. However, the etiology and pathology of the disease remain largely unexplored. Recently, the synaptopathology and the dysregulated synaptic plasticity and function have emerging as intriguing and prominent biological mechanisms of schizophrenia pathogenesis. Synaptic plasticity is the ability of neurons to change the strength of their connections in response to internal or external stimuli, which is essential for brain development and function, learning and memory, and vast majority of behavior responses relevant to psychiatric diseases including schizophrenia. Here, we reviewed molecular and cellular mechanisms of the multiple forms synaptic plasticity, and the functional regulations of schizophrenia-risk factors including disease susceptible genes and environmental alterations on synaptic plasticity and animal behavior. Recent genome-wide association studies have provided fruitful findings of hundreds of risk gene variances associated with schizophrenia, thus further clarifying the role of these disease-risk genes in synaptic transmission and plasticity will be beneficial to advance our understanding of schizophrenia pathology, as well as the molecular mechanism of synaptic plasticity.

Defect-Engineered Dzyaloshinskii-Moriya Interaction and Electric-Field-Switchable Topological Spin Texture in SrRuO3.

In situ electrical control of the Dzyaloshinskii-Moriya interaction (DMI) is one of the central but challenging goals toward skyrmion-based device applications. An atomic design of defective interfaces in spin-orbit-coupled transition-metal oxides can be an appealing strategy to achieve this goal. In this work, by utilizing the distinct formation energies and diffusion barriers of oxygen vacancies at SrRuO3 /SrTiO3 (001), a sharp interface is constructed between oxygen-deficient and stoichiometric SrRuO3 . This interfacial inversion-symmetry breaking leads to a sizable DMI, which can induce skyrmionic magnetic bubbles and the topological Hall effect in a more than 10 unit-cell-thick SrRuO3 . This topological spin texture can be reversibly manipulated through the migration of oxygen vacancies under electric gating. In particular, the topological Hall signal can be deterministically switched ON and OFF. This result implies that the defect-engineered topological spin textures may offer an alternate perspective for future skyrmion-based memristor and synaptic devices.

Soliton-Mediated Magnetic Reversal in an All-Oxide-Based Synthetic Antiferromagnetic Superlattice.

All-oxide-based synthetic antiferromagnets (SAFs) are attracting intense research interest due to their superior tunability and great potentials for antiferromagnetic spintronic devices. In this work, using the La2/3Ca1/3MnO3/CaRu1/2Ti1/2O3 (LCMO/CRTO) superlattice as a model SAF, we investigated the layer-resolved magnetic reversal mechanism by polarized neutron reflectivity. We found that the reversal of LCMO layer moments is mediated by nucleation, expansion, and shrinkage of a magnetic soliton. This unique magnetic reversal process creates a reversed magnetic configuration of the SAF after a simple field cycling. Therefore, it can enable vertical data transfer from the bottom to the top of the superlattice. The physical origin of this intriguing magnetic reversal process could be attributed to the cooperation of the surface spin-flop effect and enhanced uniaxial magnetic anisotropy of the bottom LCMO layer. This work may pave a way to utilize all-oxide-based SAFs for three-dimensional spintronic devices with vertical data transfer and high-density data storage.

Misfit Relaxation Mechanisms and Domain Ordering in Anisotropically Strained Manganite Thin Films.

The evolution of anisotropic strain in epitaxial Pr0.5Sr0.5MnO3 films grown on (LaAlO3)0.3(SrAl0.5Ta0.5O3)0.7(110) substrates has been characterized by off-specular X-ray reciprocal space mappings on the (130), (310), (222), and (222̅) reflections in the scattering zone containing the [110] axis. We demonstrate that a multistage hierarchical structural evolution (single-domain-like structure, domain ordering, twin domains, and/or periodic structural modulations) occurs as the film thickness increases, and the structural modulation between the two transverse in-plane [11̅0] and [001] directions is quite different due to the monoclinic distortion of the film. We then show the relationship between the distribution of diffraction spots in reciprocal space and their corresponding domain configurations in real space under various thicknesses, which is closely correlated with thickness-dependent magnetic and magnetotransport properties. More importantly, the distribution and annihilation dynamics of the domain ordering are imaged utilizing home-built magnetic force microscope, revealing that the structural domains tilted toward either the [001] or [001̅] direction are arranged along the [11̅1] and [1̅11] crystal orientations. The direct visualization and dynamics of anisotropic-strain-related domain ordering will open a new path toward the control and manipulation of domain engineering in strongly correlated perovskite oxide films.

Uniaxial Strain-Controlled Ground States in Manganite Films.

Strongly correlated perovskite oxides exhibit a plethera of intriguing phenomena and stimulate a great potential for multifunctional device applications. Utilizing tunable uniaxial strain, rather than biaxial or anisotropic strain, delivered from the crystallography of a single crystal substrate to modify the ground state of strongly correlated perovskite oxides has rarely been addressed for phase-space control. Here, we show that the physical properties of La2/3Ca1/3MnO3 (LCMO) films are remarkably different depending on the crystallographic orientations of the orthorhombic NdGaO3 (NGO) substrates. More importantly, the antiferromagnetic charge-ordered insulating (COI) phase induced in the (100) or (001)-oriented LCMO films can be dramatically promoted (or suppressed) by a uniaxial tensile (or compressive) bending stress along the in-plane [010] direction. By contrast, the COI phase is nearly unaffected along the other transverse in-plane directions. Results from scanning transmission electron microscopy reveal that the (100)- or (001)-oriented LCMO films are uniaxially tensile strained along the [010] direction, while the LCMO/NGO(010) and LCMO/NGO(110) films remaining as a bulklike ferromagnetic metallic state exhibit a different strain state. Density functional theory calculations further reveal that the cooperatively increased Jahn-Teller distortion and charge ordering may be indispensible for the inducing and promoting of the COI phase. These findings provide a path to understand the correlation between local and extended structural distortions imparted by coherent epitaxy and the electronic states for quantum phase engineering.

Robust Ferroelectric Properties in (K,Na)NbO3-Based Lead-Free Films via a Self-Assembled Nanocomposite Approach.

(K,Na)NbO3-based lead-free ferroelectric materials are highly desired in modern electronic applications and have long been considered as a strong candidate for replacing (Pb,Zr)TiO3, but most of them are deficient in large remnant polarization and decent thermal stability. Here, a unique lead-free 0.95(K0.49Na0.49Li0.02)(Nb0.8Ta0.2)O3-0.05CaZrO3 with 2 wt % MnO2 addition (KNNLT-CZ-M) ferroelectric film with special nanocomposite structures grown on La0.7Sr0.3MnO3-coated SrTiO3(001) substrate is demonstrated. The KNNLT-CZ-M films display excellent ferroelectricity with a large twice remnant polarization of 64.91 µC/cm2, a superior thermal stability of ferroelectricity from -196 to 300 °C, and a high Curie temperature of 400 °C. These robust performances could be attributed to the densely arranged self-assembled nanocolumns (∼10 nm in diameter) in the films, which can vertically strain the matrix and enhance its b/a ratio. The formation of the nanocolumns critically depends on the CaZrO3 component. Our results may help the design of a new type of lead-free ferroelectric films and promote their potential applications in microelectronic devices.

Enhanced Enzymatic Hydrolysis and Lignin Extraction of Wheat Straw by Triethylbenzyl Ammonium Chloride/Lactic Acid-Based Deep Eutectic Solvent Pretreatment.

Efficient and feasible pretreatment of lignocellulosic biomass waste is an important prerequisite step to promote subsequent enzymatic hydrolysis and enhance the economics of biofuels production. This study focuses on the pretreatment of wheat straw (WS) with triethylbenzyl ammonium chloride/lactic acid (TEBAC/LA)-based deep eutectic solvents to enhance biomass fractionation and lignin extraction. Effects of pretreatment time, temperature, and TEBAC/LA molar ratio on pretreatment were evaluated systematically. Results suggested that 89.06 ± 1.05% of cellulose and 71.00 ± 1.03% of xylan were hydrolyzed with enzyme loadings of 35 FPU cellulase and 82 CBU ß-glucosidase (per gram of dry biomass) after pretreatment by TEBAC/LA (1:9) at 373 K for 10 h. A total monosaccharide yield of 0.550 g/g WS (91.27% of the theoretical yield) was achieved with 79.73 ± 0.93% of lignin removal. Furthermore, the 1H-13C two-dimensional heteronuclear single quantum correlation (2D-HSQC) NMR spectroscopy showed that the regenerated lignin (75.69 ± 1.32% purity) was mainly composed of the syringyl units and the guaiacyl units. Overall, the results in this study provide an effective and facile pretreatment method for lignocellulosic biomass waste to enhance enzymatic hydrolysis saccharification.

Interfacial Engineering of Ferromagnetism in Epitaxial Manganite/Ruthenate Superlattices via Interlayer Chemical Doping.

Interfacial charge transfer and structural proximity effects are the two essential routes to trigger and tune numerous functionalities of perovskite oxide heterostructures. However, the cooperation and competition of these two interfacial effects in one epitaxial system have not been fully understood. Herein, we fabricate a series of La0.67Ca0.33MnO3/CaRuO3 superlattices and introduce various chemical doping in the nonmagnetic CaRuO3 interlayers. We found that Ti, Sr, and La doping in the CaRuO3 layer can effectively tune the interfacial charge transfer and octahedral rotation, thus modulating the ferromagnetism of the superlattices. Specifically, the B-site Ti doping depletes the Ru 4d band and suppresses the interfacial charge transfer, leading to a decay of ferromagnetic Curie temperature ( TC). In contrast, the A-site Sr doping maintains a sizable charge transfer and meanwhile suppresses the octahedral rotation, which facilitates ferromagnetism and significantly enhances the TC up to 291 K. The La doping turns out to localize the itinerant electrons in the CaRuO3 layer, which suppresses both the interfacial charge transfer and ferromagnetism. The observed intriguing interfacial engineering of magnetism would pave a new way to understand the collective effects of interfacial charge transfer and structural proximity on the physical properties of oxide heterostructures.

Induced Formation of Structural Domain Walls and Their Confinement on Phase Dynamics in Strained Manganite Thin Films.

Domain walls (DWs) in strongly correlated materials have provided fertile ground for the discovery of exotic phenomena, and controlling the formation of DWs is still a challenge. Here, it is demonstrated that a new type of structural DW can be induced in a series of manganite thin films, which are engineered to achieve a robust charge-ordering insulating (COI) ground state by selecting various films and substrates. The monoclinic domains are somewhat irregular in shape, and the corresponding DWs, taking the shape of closed loops, are ferromagnetic and metallic (FMM) at low temperatures. Remarkably, the DWs exhibit little dependence on temperature or magnetic field, due to the structural origins of the domains. Additionally, using magnetic force microscopy, the role played by DWs in the dynamics of the COI and FMM phases at the mesoscopic scale is revealed. They function as barriers, strictly confining the phase dynamics within each domain, reflecting the strong coupling of electronic phases with the lattice. Each domain exhibits binary occupation by a single pure phase, resulting in a quasi-periodic phase separation. The universal behaviors of the multiple engineered films elucidate the possibility of controlling the formation of DWs and tuning phase dynamics through DW design.