Circuit-based intervention corrects excessive dentate gyrus output in the fragile X mouse model.

Abnormal cellular and circuit excitability is believed to drive many core phenotypes in fragile X syndrome (FXS). The dentate gyrus is a brain area performing critical computations essential for learning and memory. However, little is known about dentate circuit defects and their mechanisms in FXS.

Circuit-based intervention corrects excessive dentate gyrus output in the Fragile X mouse model.

Abnormal cellular and circuit excitability is believed to drive many core phenotypes in fragile X syndrome (FXS). The dentate gyrus is a brain area performing critical computations essential for learning and memory. However, little is known about dentate circuit defects and their mechanisms in FXS.

FMRP regulates GABA receptor channel activity to control signal integration in hippocampal granule cells.

Fragile X syndrome, the most common inherited form of intellectual disability, is caused by loss of fragile X mental retardation protein (FMRP). GABAergic system dysfunction is one of the hallmarks of FXS, yet the underlying mechanisms remain poorly understood. Here, we report that FMRP interacts with GABA receptor (GABAR) and modulates its single-channel activity.

Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model.

Among most prevalent deficits in individuals with Fragile X syndrome (FXS) is hypersensitivity to sensory stimuli and somatosensory alterations. Whether dysfunction in peripheral sensory system contributes to these deficits remains poorly understood. Satellite glial cells (SGCs), which envelop sensory neuron soma, play critical roles in regulating neuronal function and excitability.

Hyperexcitability of Sensory Neurons in Fragile X Mouse Model.

Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability in KO mice, manifested by markedly increased action potential (AP) firing rate and decreased threshold.

Channelopathies in fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein-protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology.

Satellite glial cells promote regenerative growth in sensory neurons.

Peripheral sensory neurons regenerate their axon after nerve injury to enable functional recovery. Intrinsic mechanisms operating in sensory neurons are known to regulate nerve repair, but whether satellite glial cells (SGC), which completely envelop the neuronal soma, contribute to nerve regeneration remains unexplored. Using a single cell RNAseq approach, we reveal that SGC are distinct from Schwann cells and share similarities with astrocytes.

Voltage-Independent SK-Channel Dysfunction Causes Neuronal Hyperexcitability in the Hippocampus of Knock-Out Mice.

Neuronal hyperexcitability is one of the major characteristics of fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent potassium (K)-channel dysfunction in hyperexcitability of CA3 pyramidal neurons in knock-out (KO) mice. We observed a reduction of voltage-independent small conductance calcium (Ca)-activated K (SK) currents in both male and female mice, leading to decreased action potential (AP) threshold and reduced medium afterhyperpolarization.

Increased Persistent Sodium Current Causes Neuronal Hyperexcitability in the Entorhinal Cortex of Fmr1 Knockout Mice.

Altered neuronal excitability is one of the hallmarks of fragile X syndrome (FXS), but the mechanisms underlying this critical neuronal dysfunction are poorly understood. Here, we find that pyramidal cells in the entorhinal cortex of Fmr1 KO mice, an established FXS mouse model, display a decreased AP threshold and increased neuronal excitability. The AP threshold changes in Fmr1 KO mice are caused by increased persistent sodium current (INaP).

The Formation of Aberrant Collateral Vessels during Coronary Arteriogenesis in Dog Heart.

We previously reported excessive growth of collateral vessels in the dog heart during arteriogenesis induced by implantation of an ameroid constrictor around the circumflex branch of the left coronary artery. In the present study, using histology and immunocofocal microscopy, we further investigated how these aberrant collateral vessels form. By comparison with mature collateral vessels the following findings were made: perivascular space was very narrow where damage of the perivascular myocardium occurred; the neointima was very thick, resulting in a very small lumen; elastica van Gieson staining revealed the absence of the internal elastic lamina and of elastic fibers in the adventitia, but abundant collagen in the adventitia as well as in the neointima; smooth muscle cells of the neointima expressed less α-SM actin and little desmin; expression of the fibroblast growth factors aFGF, bFGF and platelet-derived growth factor (PDGF)-AB was observed mainly in the endothelial cells and abluminal region, but transforming growth factor-β1 was only present in the adventitia and damaged myocardium; angiogenesis in the neointima was observed in some collateral vessels expressing high levels of eNOS, and cell proliferation was mainly present in the abluminal region, but apoptosis was in the deep neointima.

Genetic upregulation of BK channel activity normalizes multiple synaptic and circuit defects in a mouse model of fragile X syndrome.

Single-channel recordings in CA3 pyramidal neurons revealed that large-conductance calcium-activated K(+) (BK) channel open probability was reduced by loss of fragile X mental retardation protein (FMRP) and that FMRP acts on BK channels by modulating the channel's gating kinetics. Fmr1/BKβ4 double knockout mice were generated to genetically upregulate BK channel activity in the absence of FMRP. Deletion of the BKβ4 subunit alleviated reduced BK channel open probability via increasing BK channel open frequency, but not through prolonging its open duration.

Nitric Oxide Increases Arterial Endotheial Permeability through Mediating VE-Cadherin Expression during Arteriogenesis.

Macrophage invasion is an important event during arteriogenesis, but the underlying mechanism is still only partially understood. The present study tested the hypothesis that nitric oxide (NO) and VE-cadherin, two key mediators for vascular permeability, contribute to this event in a rat ischemic hindlimb model. In addition, the effect of NO on expression of VE-caherin and endothelial permeability was also studied in cultured HUVECs.

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures.

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation.

Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts.

The promise of using reprogrammed human neurons for disease modeling and regenerative medicine relies on the ability to induce patient-derived neurons with high efficiency and subtype specificity. We have previously shown that ectopic expression of brain-enriched microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124), promoted direct conversion of human fibroblasts into neurons. Here we show that coexpression of miR-9/9*-124 with transcription factors enriched in the developing striatum, BCL11B (also known as CTIP2), DLX1, DLX2, and MYT1L, can guide the conversion of human postnatal and adult fibroblasts into an enriched population of neurons analogous to striatal medium spiny neurons (MSNs).

Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of fragile X mental retardation protein in neurotransmission.

Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and mechanisms of these FMRP actions remain incompletely understood, and the role of FMRP in regulating synaptic release probability and presynaptic function remains debated.

FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels.

Loss of FMRP causes fragile X syndrome (FXS), but the physiological functions of FMRP remain highly debatable. Here we show that FMRP regulates neurotransmitter release in CA3 pyramidal neurons by modulating action potential (AP) duration. Loss of FMRP leads to excessive AP broadening during repetitive activity, enhanced presynaptic calcium influx, and elevated neurotransmitter release.

Differential motion dynamics of synaptic vesicles undergoing spontaneous and activity-evoked endocytosis.

Synaptic vesicle exo- and endocytosis are usually driven by neuronal activity but can also occur spontaneously. The identity and differences between vesicles supporting evoked and spontaneous neurotransmission remain highly debated. Here we combined nanometer-resolution imaging with a transient motion analysis approach to examine the dynamics of individual synaptic vesicles in hippocampal terminals under physiological conditions.

Increased EID1 nuclear translocation impairs synaptic plasticity and memory function associated with pathogenesis of Alzheimer's disease.

Though loss of function in CBP/p300, a family of CREB-binding proteins, has been causally associated with a variety of human neurological disorders, such as Rubinstein-Taybi syndrome, Huntington's disease and drug addiction, the role of EP300 interacting inhibitor of differentiation 1 (EID1), a CBP/p300 inhibitory protein, in modulating neurological functions remains completely unknown. Through the examination of EID1 expression and cellular distribution, we discovered that there is a significant increase of EID1 nuclear translocation in the cortical neurons of Alzheimer's disease (AD) patient brains compared to that of control brains. To study the potential effects of EID1 on neurological functions associated with learning and memory, we generated a transgenic mouse model with a neuron-specific expression of human EID1 gene in the brain.

Requirement of phospholipase C and protein kinase C in cholecystokinin-mediated facilitation of NMDA channel function and anxiety-like behavior.

Although cholecystokinin (CCK) has long been known to exert anxiogenic effects in both animal anxiety models and humans, the underlying cellular and molecular mechanisms are ill-defined. CCK interacts with CCK-1 and CCK-2 receptors resulting in up-regulation of phospholipase C (PLC) and protein kinase C (PKC). However, the roles of PLC and PKC in CCK-mediated anxiogenic effects have not been determined.

The diverse functions of short-term plasticity components in synaptic computations.

Short-term plasticity (STP) comprises several rapid synaptic processes that operate on millisecond-to-minute timescales and modulate synaptic efficacy in an activity-dependent manner. Facilitation and augmentation are two major STP components in central synapses that work to enhance synaptic strength, while various forms of short-term depression work to decrease it. These multiple components of STP interact to perform a variety of synaptic computations.

Short-term plasticity optimizes synaptic information transmission.

Short-term synaptic plasticity (STP) is widely thought to play an important role in information processing. This major function of STP has recently been challenged, however, by several computational studies indicating that transmission of information by dynamic synapses is broadband, i.e.

Abnormal presynaptic short-term plasticity and information processing in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading genetic cause of autism. It is associated with the lack of fragile X mental retardation protein (FMRP), a regulator of protein synthesis in axons and dendrites. Studies on FXS have extensively focused on the postsynaptic changes underlying dysfunctions in long-term plasticity.

The role of presynaptic dynamics in processing of natural spike trains in hippocampal synapses.

Short-term plasticity (STP) represents a key neuronal mechanism of information processing. In excitatory hippocampal synapses, STP serves as a high-pass filter optimized for the transmission of information-carrying place-field discharges. This STP filter enables synapses to perform a highly nonlinear, switch-like operation permitting the passage and amplification of signals with place-field-like characteristics.

Cholecystokinin facilitates glutamate release by increasing the number of readily releasable vesicles and releasing probability.

Cholecystokinin (CCK), a neuropeptide originally discovered in the gastrointestinal tract, is abundantly distributed in the mammalian brains including the hippocampus. Whereas CCK has been shown to increase glutamate concentration in the perfusate of hippocampal slices and in purified rat hippocampal synaptosomes, the cellular and molecular mechanisms whereby CCK modulates glutamatergic function remain unexplored. Here, we examined the effects of CCK on glutamatergic transmission in the hippocampus using whole-cell recordings from hippocampal slices.