Germline PTEN genotype-dependent phenotypic divergence during the early neural developmental process of forebrain organoids.

PTEN germline mutations account for ~0.2-1% of all autism spectrum disorder (ASD) cases, as well as ~17% of ASD patients with macrocephaly, making it one of the top ASD-associated risk genes. Individuals with germline PTEN mutations receive the molecular diagnosis of PTEN Hamartoma Tumor Syndrome (PHTS), an inherited cancer predisposition syndrome, about 20-23% of whom are diagnosed with ASD. We generated forebrain organoid cultures from gene-edited isogenic human induced pluripotent stem cells (hiPSCs) harboring a PTENG132D (ASD) or PTENM134R (cancer) mutant allele to model how these mutations interrupt neurodevelopmental processes. Here, we show that the PTENG132D allele disrupts early neuroectoderm formation during the first several days of organoid generation, and results in deficient electrophysiology. While organoids generated from PTENM134R hiPSCs remained morphologically similar to wild-type organoids during this early stage in development, we observed disrupted neuronal differentiation, radial glia positioning, and cortical layering in both PTEN-mutant organoids at the later stage of 72+ days of development. Perifosine, an AKT inhibitor, reduced over-activated AKT and partially corrected the abnormalities in cellular organization observed in PTENG132D organoids. Single cell RNAseq analyses on early-stage organoids revealed that genes related to neural cell fate were decreased in PTENG132D mutant organoids, and AKT inhibition was capable of upregulating gene signatures related to neuronal cell fate and CNS maturation pathways. These findings demonstrate that different PTEN missense mutations can have a profound impact on neurodevelopment at diverse stages which in turn may predispose PHTS individuals to ASD. Further study will shed light on ways to mitigate pathological impact of PTEN mutants on neurodevelopment by stage-specific manipulation of downstream PTEN signaling components.

Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response.

Epilepsy, a common neurological disorder, is featured with recurrent seizures. Its underlying pathological mechanisms remain elusive. Here, we provide evidence for loss of neogenin (NEO1), a coreceptor for multiple ligands, including netrins and bone morphological proteins, in the development of epilepsy. NEO1 is reduced in hippocampi from patients with epilepsy based on transcriptome and proteomic analyses. Neo1 knocking out (KO) in mouse brains displays elevated epileptiform spikes and seizure susceptibility. These phenotypes were undetectable in mice, with selectively depleted NEO1 in excitatory (NeuroD6-Cre+) or inhibitory (parvalbumin+) neurons, but present in mice with specific hippocampal astrocytic Neo1 KO. Additionally, neurons in hippocampal dentate gyrus, a vulnerable region in epilepsy, in mice with astrocyte-specific Neo1 KO show reductions in inhibitory synaptic vesicles and the frequency of miniature inhibitory postsynaptic current(mIPSC), but increase of the duration of miniature excitatory postsynaptic current and tonic NMDA receptor currents, suggesting impairments in both GABAergic transmission and extracellular glutamate clearance. Further proteomic and cell biological analyses of cell-surface proteins identified GLAST, a glutamate-aspartate transporter that is marked reduced in Neo1 KO astrocytes and the hippocampus. NEO1 interacts with GLAST and promotes GLAST surface distribution in astrocytes. Expressing NEO1 or GLAST in Neo1 KO astrocytes in the hippocampus abolishes the epileptic phenotype. Taken together, these results uncover an unrecognized pathway of NEO1-GLAST in hippocampal GFAP+ astrocytes, which is critical for GLAST surface distribution and function, and GABAergic transmission, unveiling NEO1 as a valuable therapeutic target to protect the brain from epilepsy.

An ErbB4-Positive Neuronal Network in the Olfactory Bulb for Olfaction.

Olfactory information is relayed and processed in the olfactory bulb (OB). Mitral cells (MCs), the principal output excitatory neurons of the OB, are controlled by multiple types of interneurons. However, mechanisms that regulate the activity of OB interneurons are not well understood. We provide evidence that the transmembrane tyrosine kinase ErbB4 is selectively expressed in subsets of OB inhibitory neurons in both male and female mice. ErbB4-positive (ErbB4+) neurons are mainly located in the glomerular layer (GL) and granule cell layer (GCL) and do not express previously defined markers. Optogenetic activation of GL-ErbB4+ neurons promotes theta oscillation, whereas activation of those in the GCL generates gamma oscillations. Stimulation of OB slices with NRG1, a ligand that activates ErbB4, increases GABA transmission onto MCs, suggesting a role of OB NRG1-ErbB4 signaling in olfaction. In accord, ErbB4 mutant mice or acute inhibition of ErbB4 by a chemical genetic approach diminishes GABA transmission, reduces bulbar local field potential (LFP) power, increases the threshold of olfactory sensitivity, and impairs odor discrimination. Together these results identified a bulbar inhibitory network of ErbB4+ neurons for olfaction. Considering both NRG1 and ErbB4 are susceptibility genes for neuropsychiatric disorders, our study provides insight into pathological mechanisms of olfactory malfunctions in these disorders.Significance Statement:This study demonstrates ErbB4+ neurons are a new subset of OB inhibitory neurons in the GL and GCL that innervate MCs and ErbB4- cells. They regulate olfaction by controlling local synchrony and distinct oscillations. ErbB4 inhibition diminishes GABA transmission, reduces bulbar local field potential (LFP) power, increases the threshold of olfactory sensitivity, and impairs odor discrimination. Our results provide insight into pathophysiological mechanism of olfaction deficits in brain disorders associated with NRG1 or ErbB4 mutations.

Neuregulin 1 and ErbB4 Kinase Actively Regulate Sharp Wave Ripples in the Hippocampus.

Sharp wave ripples (SW-Rs) in the hippocampus are synchronized bursts of hippocampal pyramidal neurons (PyNs), critical for spatial working memory. However, the molecular underpinnings of SW-Rs remain poorly understood. We show that SW-Rs in hippocampal slices from both male and female mice were suppressed by neuregulin 1 (NRG1), an epidermal growth factor whose expression is enhanced by neuronal activity. Pharmacological inhibition of ErbB4, a receptor tyrosine kinase for NRG1, increases SW-R occurrence rate in hippocampal slices. These results suggest an important role of NRG1-ErbB4 signaling in regulating SW-Rs. To further test this notion, we characterized SW-Rs in freely moving male mice, chemical genetic mutant mice, where ErbB4 can be specifically inhibited by the bulky inhibitor 1NMPP1. Remarkably, SW-R occurrence was increased by 1NMPP1. We found that 1NMPP1 increased the firing rate of PyN neurons, yet disrupted PyN neuron dynamics during SW-R events. Furthermore, 1NMPP1 increased SW-R occurrence during both nonrapid eye movement (NREM) sleep states and wake states with a greater impact on SW-Rs during wake states. In accord, spatial working memory was attenuated in male mice. Together these results indicate that dynamic activity of ErbB4 kinase is critical to SW-Rs and spatial working memory. This study reveals a novel regulatory mechanism of SW-Rs and a novel function of the NRG1-ErbB4 signaling.SIGNIFICANCE STATEMENT Sharp wave ripples (SW-Rs) are a hippocampal event, important for memory functioning. Yet the molecular pathways that regulate SW-Rs remain unclear. Neuregulin 1 (NRG1), previously known to be increased in pyramidal neuron's (PyNs) in an activity dependent manner, signals to its receptor, ErbB4 kinase, that is in important regulator of GABAergic transmission and long-term potentiation in the hippocampus. Our findings demonstrate that SW-Rs are regulated by this signaling pathway in a dynamic manner. Not only so, we show that this signaling pathway is dynamically needed for spatial working memory. These data suggest a molecular signaling pathway, NRG1-ErbB4, that regulates an important network event of the hippocampus, SW-Rs, that underlies memory functioning.

Research on Electric Field-Induced Catalysis Using Single-Molecule Electrical Measurement.

The role of catalysis in controlling chemical reactions is crucial. As an important external stimulus regulatory tool, electric field (EF) catalysis enables further possibilities for chemical reaction regulation. To date, the regulation mechanism of electric fields and electrons on chemical reactions has been modeled. The electric field at the single-molecule electronic scale provides a powerful theoretical weapon to explore the dynamics of individual chemical reactions. The combination of electric fields and single-molecule electronic techniques not only uncovers new principles but also results in the regulation of chemical reactions at the single-molecule scale. This perspective focuses on the recent electric field-catalyzed, single-molecule chemical reactions and assembly, and highlights promising outlooks for future work in single-molecule catalysis.

A Role of Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) in Astrocytic Aß Clearance.

Amyloid-ß (Aß) deposition occurs years before cognitive symptoms appear and is considered a cause of Alzheimer's disease (AD). The imbalance of Aß production and clearance leads to Aß accumulation and Aß deposition. Increasing evidence indicates an important role of astrocytes, the most abundant cell type among glial cells in the brain, in Aß clearance. We explored the role of low-density lipoprotein receptor-related protein 4 (LRP4), a member of the LDLR family, in AD pathology. We show that Lrp4 is specifically expressed in astrocytes and its levels in astrocytes were higher than those of Ldlr and Lrp1, both of which have been implicated in Aß uptake. LRP4 was reduced in postmortem brain tissues of AD patients. Genetic deletion of the Lrp4 gene augmented Aß plaques in 5xFAD male mice, an AD mouse model, and exacerbated the deficits in neurotransmission, synchrony between the hippocampus and PFC, and cognition. Mechanistically, LRP4 promotes Aß uptake by astrocytes likely by interacting with ApoE. Together, our study demonstrates that astrocytic LRP4 plays an important role in Aß pathology and cognitive function.SIGNIFICANCE STATEMENT This study investigates how astrocytes, a type of non-nerve cells in the brain, may contribute to Alzheimer's disease (AD) development. We demonstrate that the low-density lipoprotein receptor-related protein 4 (LRP4) is reduced in the brain of AD patients. Mimicking the reduced levels in an AD mouse model exacerbates cognitive impairment and increases amyloid aggregates that are known to damage the brain. We show that LRP4 could promote the clearance of amyloid protein by astrocytes. Our results reveal a previously unappreciated role of LRP4 in AD development.

Single-Molecule Charge-Transport Modulation Induced by Steric Effects of Side Alkyl Chains.

The experimental investigation of side-chain effects on intramolecular charge transport in π-conjugated molecules is essential but remains challenging. Herein, the dependence of intra-molecular conductance on the nature of branching alkyl chains is investigated through a combination of the scanning tunneling microscope break junction (STM-BJ) technique and density functional theory. Three thiophene-flanked diketopyrrolopyrrole (DPP) derivatives with different branching alkyl chains (isopentane, 3-methylheptane, and 9-methylnonadecane) are used with phenylthiomethyl groups as the anchoring groups. The results of single-molecule conductance measurements show that as the alkyl chain becomes longer, the torsional angles between the aromatic rings increase due to steric crowding, and therefore, the molecular conductance of DPP decreases due to reduction in conjugation. Both theoretical simulations and 1 H NMR spectra demonstrate that the planarity of the DPPs is directly reduced after introducing longer branching alkyl chains, which leads to a reduced conductance. This work indicates that the effect of the insulating side chain on the single-molecule conductance cannot be neglected, which should be considered for the design of future organic semiconducting materials.

Anti-resonance features of destructive quantum interference in single-molecule thiophene junctions achieved by electrochemical gating.

Controlling the electrical conductance and in particular the occurrence of quantum interference in single-molecule junctions through gating effects has potential for the realization of high-performance functional molecular devices. In this work we used an electrochemically gated, mechanically controllable break junction technique to tune the electronic behaviour of thiophene-based molecular junctions that show destructive quantum interference features. By varying the voltage applied to the electrochemical gate at room temperature, we reached a conductance minimum that provides direct evidence of charge transport controlled by an anti-resonance arising from destructive quantum interference. Our molecular system enables conductance tuning close to two orders of magnitude within the non-faradaic potential region, which is significantly higher than that achieved with molecules not showing destructive quantum interference. Our experimental results, interpreted using quantum transport theory, demonstrate that electrochemical gating is a promising strategy for obtaining improved in situ control over the electrical performance of interference-based molecular devices.

Regulation of Synapse Development by Vgat Deletion from ErbB4-Positive Interneurons.

GABA signaling has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA activity die prematurely. Here, we studied synapse development by ablating vesicular GABA transporter (Vgat) in ErbB4+ interneurons. We show that inhibitory axo-somatic synapses onto pyramidal neurons vary from one cortical layer to another; however, inhibitory synapses on axon initial segments (AISs) were similar across layers. Conversely, parvalbumin-positive (PV+)/ErbB4+ interneurons and PV-only interneurons receive a higher number of inhibitory synapses from PV+ErbB4+ interneurons compared with ErbB4-only interneurons. Vgat deletion from ErbB4+ interneurons reduced axo-somatic or axo-axonic synapses from PV+ErbB4+ interneurons onto excitatory neurons. This effect was associated with corresponding changes in neurotransmission. However, the Vgat mutation seemed to have little effect on inhibitory synapses onto PV+ and/or ErbB4+ interneurons. Interestingly, perineuronal nets, extracellular matrix structures implicated in maturation, survival, protection, and plasticity of PV+ interneurons, were increased in the cortex of ErbB4-Vgat-/- mice. No apparent difference was observed between males and females. These results demonstrate that Vgat of ErbB4+ interneurons is essential for the development of inhibitory synapses onto excitatory neurons and suggest a role of GABA in circuit assembly.SIGNIFICANCE STATEMENT GABA has been implicated in neural development, but in vivo genetic evidence is missing because mutant mice lacking GABA die prematurely. Here, we ablated Vgat in ErbB4+ interneurons in an inducible manner. We provide evidence that the formation of inhibitory and excitatory synapses onto excitatory neurons requires Vgat in interneurons. In particular, inhibitory axo-somatic and axo-axonic synapses are more vulnerable. Our results suggest a role of GABA in circuit assembly.

Sarcoglycan Alpha Mitigates Neuromuscular Junction Decline in Aged Mice by Stabilizing LRP4.

During aging, acetylcholine receptor (AChR) clusters become fragmented and denervated at the neuromuscular junction (NMJ). Underpinning molecular mechanisms are not well understood. We showed that LRP4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylation, suggesting compromised agrin-LRP4-MuSK signaling in aged muscles. Transgenic expression of LRP4 in muscles alleviated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. LRP4 ubiquitination was augmented in aged muscles, suggesting increased LRP4 degradation as a mechanism for reduced LRP4. We found that sarcoglycan α (SGα) interacted with LRP4 and delayed LRP4 degradation in cotransfected cells. AAV9-mediated expression of SGα in muscles mitigated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. These observations support a model where compromised agrin-LRP4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SGα in stabilizing LRP4 for NMJ stability in aged mice.SIGNIFICANCE STATEMENT This study provides evidence that LRP4, a receptor of agrin that is critical for NMJ formation and maintenance, is reduced at protein level in aged muscles. Transgenic expression of LRP4 in muscles ameliorates AChR fragmentation and denervation and improves neuromuscular transmission in aged mice, demonstrating a critical role of the agrin-LRP4-MuSK signaling. Our study also reveals a novel function of SGα to prevent LRP4 degradation in aged muscles. Finally, we show that NMJ decline in aged mice can be mitigated by AAV9-mediated expression of SGα in muscles. These observations provide insight into pathological mechanisms of age-related NMJ decline and suggest that improved agrin-LRP4-MuSK signaling may be a target for potential therapeutic intervention.

Light-Driven Reversible Intermolecular Proton Transfer at Single-Molecule Junctions.

Photoresponsive molecular systems are essential for molecular optoelectronic devices, but most molecular building blocks are non-photoresponsive. Employed here is a photoinduced proton transfer (PIPT) strategy to control charge transport through single-molecule azulene junctions with visible light under ambient conditions, which leads to a reversible and controllable photoresponsive molecular device based on non-photoresponsive molecules and a photoacid. Also demonstrated is the application of PIPT in two single-molecule AND gate and OR gate devices with electrical signal as outputs.

Muscle Yap Is a Regulator of Neuromuscular Junction Formation and Regeneration.

Yes-associated protein (Yap) is a major effector of the Hippo pathway that regulates cell proliferation and differentiation during development and restricts tissue growth in adult animals. However, its role in synapse formation remains poorly understood. In this study, we characterized Yap's role in the formation of the neuromuscular junction (NMJ). In HSA-Yap-/- mice where Yap was mutated specifically in muscle cells, AChR clusters were smaller and were distributed in a broader region in the middle of muscle fibers, suggesting that muscle Yap is necessary for the size and location of AChR clusters. In addition, HSA-Yap-/- mice also exhibited remarkable presynaptic deficits. Many AChR clusters were not or less covered by nerve terminals; miniature endplate potential frequency was reduced, which was associated with an increase in paired-pulse facilitation, indicating structural and functional defects. In addition, muscle Yap mutation prevented reinnervation of denervated muscle fibers. Together, these observations indicate a role of muscle Yap in NMJ formation and regeneration. We found that ß-catenin was reduced in the cytoplasm and nucleus of mutant muscles, suggesting compromised ß-catenin signaling. Both NMJ formation and regeneration deficits of HSA-Yap-/- mice were ameliorated by inhibiting ß-catenin degradation, further corroborating a role of ß-catenin or Wnt-dependent signaling downstream of Yap to regulate NMJ formation and regeneration.SIGNIFICANCE STATEMENT This paper explored the role of Yes-associated protein (Yap) in neuromuscular junction (NMJ) formation and regeneration. Yap is a major effector of the Hippo pathway that regulates cell proliferation and differentiation during development and restricts tissue growth in adult animals. However, its role in synapse formation remains poorly understood. We provide evidence that muscle Yap mutation impairs both postsynaptic and presynaptic differentiation and function and inhibits NMJ regeneration after nerve injury, indicating a role of muscle Yap in these events. Further studies suggest compromised ß-catenin signaling as a potential mechanism. Both NMJ formation and regeneration deficits of HSA-Yap-/- mice were ameliorated by inhibiting ß-catenin degradation, corroborating a role of ß-catenin or Wnt-dependent signaling downstream of Yap to regulate NMJ formation and regeneration.

Synthesis and Characterization of α-ZrP@CHI Drug Deliver System.

This paper described the controlled synthesis and release properties of a new kind of multifunctional drug-release system which was prepared by encapsulation of zirconium bis-(monohydrogen orthophosphate) monohydrate (α-ZrP) with chitosan (CHI). As obtained the α-ZrP@CHI nanocomposites were found to possess the structural features of both α-ZrP and CHI. The release properties of the α-ZrP@CHI nanocomposites were evaluated using Gentamicin sulfate as the model drug. And α-ZrP@CHI composites showed a prolonged drug release time compared with α-ZrP, which can be attributed to the unique lamellar structure and the encapsulation with CHI. The controlled synthesis of α-ZrP@CHI nanocomposite thus provided a new opportunity for future development of delivery vehicles.

Heterosynaptic long-term depression mediated by ATP released from astrocytes.

Heterosynaptic long-term depression (hLTD) at untetanized synapses accompanying the induction of long-term potentiation (LTP) spatially sharpens the activity-induced synaptic potentiation; however, the underlying mechanism remains unclear. We found that hLTD in the hippocampal CA1 region is caused by stimulation-induced ATP release from astrocytes that suppresses transmitter release from untetanized synaptic terminals via activation of P2Y receptors. Selective stimulation of astrocytes expressing channelrhodopsin-2, a light-gated cation channel permeable to Ca(2+) , resulted in LTD of synapses on neighboring neurons. This synaptic modification required Ca(2+) elevation in astrocytes and activation of P2Y receptors, but not N-methyl-D-aspartate receptors. Furthermore, blocking P2Y receptors or buffering astrocyte intracellular Ca(2+) at a low level prevented hLTD without affecting LTP induced by SC stimulation. Thus, astrocyte activation is both necessary and sufficient for mediating hLTD accompanying LTP induction, strongly supporting the notion that astrocytes actively participate in activity-dependent synaptic plasticity of neural circuits.

Chemical Sensors using Single-Molecule Electrical Measurements.

Driven by the digitization and informatization of contemporary society, electrical sensors are developing toward minimal structure, intelligent function, and high detection resolution. Single-molecule electrical measurement techniques have been proven to be capable of label-free molecular recognition and detection, which opens a new strategy for the design of efficient single-molecule detection sensors. In this review, we outline the main advances and potentials of single-molecule electronics for qualitative identification and recognition assays at the single-molecule level. Strategies for single-molecule electro-sensing and its main applications are reviewed, mainly in the detection of ions, small molecules, oligomers, genetic materials, and proteins. This review summarizes the remaining challenges in the current development of single-molecule electrical sensing and presents some potential perspectives for this field.

Simultaneous Electrical and Mechanical Characterization of Single-Molecule Junctions Using AFM-BJ Technique.

The fabrication and characterization of single-molecule junctions provide a unique platform to study the physical phenomena of a single molecule, and the electrical characterization enables us to understand the electrical transport properties of a single molecule and guide the fabrication of molecular electronic devices. However, the electrical characterization of single-molecule junctions is sometimes insufficient to extract the structural information on single-molecule junctions, and an alternate method to address this problem is to characterize the mechanical properties of single-molecule junctions. Simultaneous measurement of mechanical and electrical properties can provide complementary information on single molecules to analyze the correlations of their electrical and mechanical properties in the evolution of single-molecule junctions. In this mini-review, we summarize the progress on the simultaneous characterizations of mechanical and electrical properties for single-molecule junctions, and discuss the challenges and perspectives of this research area.

Molecular Strategies for Intensity-Dependent Olfactory Processing in Caenorhabditis elegans.

Various odorants trigger complex animal behaviors across species in both quality- and quantity-dependent manners. However, how the intensity of olfactory input is encoded remains largely unknown. Here we report that isoamyl alcohol (IAA) induces bi-directional currents through a Gα- guanylate cyclase (GC)- cGMP signaling pathway in Caenorhabditis elegans olfactory neuron amphid wing "C" cell (AWC), while two opposite cGMP signaling pathways are responsible for odor-sensing in olfactory neuron amphid wing "B" cell (AWB): (1) a depolarizing Gα (GPA-3)- phosphodiesterase (PDE) - cGMP pathway which can be activated by low concentrations of isoamyl alcohol (IAA), and (2) a hyperpolarizing Gα (ODR-3)- GC- cGMP pathway sensing high concentrations of IAA. Besides, IAA induces Gα (ODR-3)-TRPV(OSM-9)-dependent currents in amphid wing "A" cell (AWA) and amphid neuron "H" cell with single ciliated sensory ending (ASH) neurons with different thresholds. Our results demonstrate that an elaborate combination of multiple signaling machineries encode the intensity of olfactory input, shedding light on understanding the molecular strategies on sensory transduction.

Solvent-molecule interaction induced gating of charge transport through single-molecule junctions.

To explore solvent gating of single-molecule electrical conductance due to solvent-molecule interactions, charge transport through single-molecule junctions with different anchoring groups in various solvent environments was measured by using the mechanically controllable break junction technique. We found that the conductance of single-molecule junctions can be tuned by nearly an order of magnitude by varying the polarity of solvent. Furthermore, gating efficiency due to solvent-molecule interactions was found to be dependent on the choice of the anchor group. Theoretical calculations revealed that the polar solvent shifted the molecular-orbital energies, based on the coupling strength of the anchor groups. For weakly coupled molecular junctions, the polar solvent-molecule interaction was observed to reduce the energy gap between the molecular orbital and the Fermi level of the electrode and shifted the molecular orbitals. This resulted in a more significant gating effect than that of the strongly coupled molecules. This study suggested that solvent-molecule interaction can significantly affect the charge transport through single-molecule junctions.

Enhanced charge transport via d(δ)-p(π) conjugation in Mo2-integrated single-molecule junctions.

A trans-dimolybdenum nicotinate (m-Mo2) complex and its isonicotinate isomer (p-Mo2) were synthesized and characterized crystallographically, and their single-molecule charge transport properties were investigated using the STM break junction (STM-BJ) technique. With a quadruply bonded Mo2 complex unit integrated into molecular backbones, the single-molecule conductance for complex molecules was increased by more than one order of magnitude compared with that of the organic π-conjugated analogues 1,4-bis(4-pyridyl)benzene (p-Ph) and 1,4-bis(3-pyridyl)benzene (m-Ph). More interestingly, unlike m-Ph, m-Mo2 with meta connected pyridyl anchors presents larger conductance than that of p-Mo2 with two para connected pyridyl groups. DFT-based transmission calculations revealed that the significant conductance enhancement of Mo2 molecules originates from the largely reduced HOMO-LUMO gap, and the unique d(δ)-p(π) conjugation between the Mo2 unit and the pyridine rings gives rise to a delocalized electronic structure that endows the Mo2 molecules with an unexpected high conductance.