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1.
Mol Psychiatry ; 26(12): 7436-7445, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34168285

RESUMEN

Suicide is a significant public health concern with complex etiology. Although the genetic component of suicide is well established, the scope of gene networks and biological mechanisms underlying suicide has yet to be defined. Previously, we reported genome-wide evidence that neurexin 1 (NRXN1), a key synapse organizing molecule, is associated with familial suicide risk. Here we present new evidence for two non-synonymous variants (rs78540316; P469S and rs199784139; H885Y) associated with increased familial risk of suicide death. We tested the impact of these variants on binding interactions with known partners and assessed functionality in a hemi-synapse formation assay. Although the formation of hemi-synapses was not altered with the P469S variant relative to wild-type, both variants increased binding to the postsynaptic binding partner, leucine-rich repeat transmembrane neuronal 2 (LRRTM2) in vitro. Our findings indicate that variants in NRXN1 and related synaptic genes warrant further study as risk factors for suicide death.


Asunto(s)
Proteínas de Unión al Calcio/genética , Moléculas de Adhesión Celular Neuronal , Moléculas de Adhesión de Célula Nerviosa/genética , Suicidio , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Unión Proteica/fisiología , Factores de Riesgo , Sinapsis/metabolismo
2.
J Neurosci ; 40(28): 5376-5388, 2020 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-32503885

RESUMEN

Missense variants in Kirrel3 are repeatedly identified as risk factors for autism spectrum disorder and intellectual disability, but it has not been reported if or how these variants disrupt Kirrel3 function. Previously, we studied Kirrel3 loss of function using KO mice and showed that Kirrel3 is a synaptic adhesion molecule necessary to form one specific type of hippocampal synapse in vivo Here, we developed an in vitro, gain-of-function assay for Kirrel3 using neuron cultures prepared from male and female mice and rats. We find that WT Kirrel3 induces synapse formation selectively between Kirrel3-expressing neurons via homophilic, transcellular binding. We tested six disease-associated Kirrel3 missense variants and found that five attenuate this synaptogenic function. All variants tested traffic to the cell surface and localize to synapses similar to WT Kirrel3. Two tested variants lack homophilic transcellular binding, which likely accounts for their reduced synaptogenic function. Interestingly, we also identified variants that bind in trans but cannot induce synapses, indicating that Kirrel3 transcellular binding is necessary but not sufficient for its synaptogenic function. Collectively, these results suggest Kirrel3 functions as a synaptogenic, cell-recognition molecule, and this function is attenuated by missense variants associated with autism spectrum disorder and intellectual disability. Thus, we provide critical insight to the mechanism of Kirrel3 function and the consequences of missense variants associated with autism and intellectual disability.SIGNIFICANCE STATEMENT Here, we advance our understanding of mechanisms mediating target-specific synapse formation by providing evidence that Kirrel3 transcellular interactions mediate target recognition and signaling to promote synapse development. Moreover, this study tests the effects of disease-associated Kirrel3 missense variants on synapse formation, and thereby, increases understanding of the complex etiology of neurodevelopmental disorders arising from rare missense variants in synaptic genes.


Asunto(s)
Hipocampo/metabolismo , Proteínas de la Membrana/genética , Mutación Missense , Neuronas/metabolismo , Sinapsis/metabolismo , Animales , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Adhesión Celular/fisiología , Células Cultivadas , Femenino , Hipocampo/citología , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratas
4.
Nat Methods ; 12(6): 568-76, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25915120

RESUMEN

We describe an engineered family of highly antigenic molecules based on GFP-like fluorescent proteins. These molecules contain numerous copies of peptide epitopes and simultaneously bind IgG antibodies at each location. These 'spaghetti monster' fluorescent proteins (smFPs) distributed well in neurons, notably into small dendrites, spines and axons. smFP immunolabeling localized weakly expressed proteins not well resolved with traditional epitope tags. By varying epitope and scaffold, we generated a diverse family of mutually orthogonal antigens. In cultured neurons and mouse and fly brains, smFP probes allowed robust, orthogonal multicolor visualization of proteins, cell populations and neuropil. smFP variants complement existing tracers and greatly increase the number of simultaneous imaging channels, and they performed well in advanced preparations such as array tomography, super-resolution fluorescence imaging and electron microscopy. In living cells, the probes improved single-molecule image tracking and increased yield for RNA-seq. These probes facilitate new experiments in connectomics, transcriptomics and protein localization.


Asunto(s)
Proteínas Luminiscentes/química , Microscopía Electrónica/métodos , Microscopía Fluorescente/métodos , Animales , Antígenos , Mapeo Encefálico , Drosophila , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Neuronas , Conformación Proteica
5.
Proc Natl Acad Sci U S A ; 108(1): 367-72, 2011 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-21173224

RESUMEN

The establishment of neuronal circuits relies on the stabilization of functionally appropriate connections and the elimination of inappropriate ones. Here we report that postsynaptic AMPA receptors play a critical role in regulating the stability of glutamatergic synapses. Removal of surface AMPA receptors leads to a decrease in the number and stability of excitatory presynaptic inputs, whereas overexpression increases synapse number and stability. Furthermore, overexpression of AMPA receptors along with Neuroligin-1 in 293T cells is sufficient to stabilize presynaptic inputs from cortical neurons onto heterologous cells. The stabilization of presynaptic inputs by AMPA receptors is not dependent on receptor-mediated current and instead relies on structural interactions mediated by the N-terminal domain of the glutamate receptor 2 (GluR2) subunit. These observations indicate that transsynaptic signaling mediated by the extracellular domain of GluR2 regulates the stability of presynaptic terminals.


Asunto(s)
Espinas Dendríticas/fisiología , Receptores AMPA/metabolismo , Transducción de Señal/fisiología , Sinapsis/fisiología , Moléculas de Adhesión Celular Neuronal/metabolismo , Línea Celular , Espinas Dendríticas/metabolismo , Electrofisiología , Humanos , Inmunohistoquímica , Receptores de N-Metil-D-Aspartato/metabolismo
6.
eNeuro ; 10(12)2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37977826

RESUMEN

Kirrel3 is a cell-adhesion molecule that instructs the formation of specific synapses during brain development in mouse and Kirrel3 variants may be risk factors for autism and intellectual disabilities in humans. Kirrel3 is predicted to undergo alternative splicing but brain isoforms have not been studied. Here, we present the first in-depth characterization of Kirrel3 isoform diversity in brain using targeted, long-read mRNA sequencing of mouse hippocampus. We identified 19 isoforms with predicted transmembrane and secreted forms and show that even rare isoforms generate detectable protein in the brain. We also analyzed publicly-available long-read mRNA databases from human brain tissue and found 11 Kirrel3 isoforms that, similar to mouse, encode transmembrane and secreted forms. In mice and humans, Kirrel3 diversity arises from alternative, independent use of protein-domain coding exons and alternative early translation-stop signals. Intriguingly, the alternatively spliced exons appear at branch points in the chordate phylogenetic tree, including one exon only found in humans and their closest living relatives, the great apes. Together, these results validate a simple pipeline for analyzing isoform diversity in genes with low expression and suggest that Kirrel3 function is fine-tuned by alternative splicing and may play a role in brain evolution.


Asunto(s)
Empalme Alternativo , Sinapsis , Ratones , Animales , Humanos , Filogenia , Sinapsis/metabolismo , Empalme Alternativo/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismo , Proteínas de la Membrana/genética
7.
medRxiv ; 2023 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-36778310

RESUMEN

Suicide is a condition resulting from complex environmental and genetic risks that affect millions of people globally. Both structural and functional studies identified the hippocampus as one of the vulnerable brain regions contributing to suicide risk. Here, we have identified the hippocampal transcriptomes, gene ontology, cell type proportions, dendritic spine morphology, and transcriptomic signature in iPSC-derived neuronal precursor cells (NPCs) and neurons in postmortem brain tissue from suicide deaths. The hippocampal tissue transcriptomic data revealed that NPAS4 gene expression was downregulated while ALDH1A2, NAAA, and MLXIPL gene expressions were upregulated in tissue from suicide deaths. The gene ontology identified 29 significant pathways including NPAS4-associated gene ontology terms "excitatory post-synaptic potential", "regulation of postsynaptic membrane potential" and "long-term memory" indicating alteration of glutamatergic synapses in the hippocampus of suicide deaths. The cell type deconvolution identified decreased excitatory neuron proportion and an increased inhibitory neuron proportion providing evidence of excitation/inhibition imbalance in the hippocampus of suicide deaths. In addition, suicide deaths had increased dendric spine density, due to an increase of thin (relatively unstable) dendritic spines, compared to controls. The transcriptomes of iPSC-derived hippocampal-like NPCs and neurons revealed 31 and 33 differentially expressed genes in NPC and neurons, respectively, of suicide deaths. The suicide-associated differentially expressed genes in NPCs were RELN, CRH, EMX2, OXTR, PARM1 and IFITM2 which overlapped with previously published results. The previously-known suicide-associated differentially expressed genes in differentiated neurons were COL1A1, THBS1, IFITM2, AQP1, and NLRP2. Together, these findings would help better understand the hippocampal neurobiology of suicide for identifying therapeutic targets to prevent suicide.

8.
R Soc Open Sci ; 10(7): 230155, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37448479

RESUMEN

There is an urgent need to address coastal dynamics as a fundamental interaction between physical and biological processes, particularly when trying to predict future biological-physical linkages under anticipated changes in environmental forcing. More integrated modelling, support for observational networks and the use of management interventions as controlled experimental exercises should now be vigorously pursued.

9.
J Biol Chem ; 285(28): 21359-65, 2010 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-20452969

RESUMEN

Acyl-CoA-binding protein (ACBP) functions both intracellularly as part of fatty acid metabolism and extracellularly as diazepam binding inhibitor, the precursor of endozepine peptides. Two of these peptides, ODN and TTN, bind to the GABA(A) receptor and modulate its sensitivity to gamma-aminobutyric acid (GABA). We have found that depolarization of mouse primary astrocytes induces the rapid release and processing of ACBP to the active peptides. We previously showed that ODN can trigger the rapid sporulation of the social amoeba Dictyostelium. Using this bioassay, we now show that astrocytes release the endozepine peptides within 10 min of exposure to the steroids cortisol, pregnenolone, pregnenolone sulfate, or progesterone. ACBP lacks a signal sequence for secretion through the endoplasmic reticulum/Golgi pathway and its secretion is not affected by addition of brefeldin A, a well known inhibitor of the classical secretion pathway, suggesting that it follows an unconventional pathway for secretion. Moreover, induction of autophagy by addition of rapamycin also resulted in rapid release of ACBP indicating that this protein uses components of the autophagy pathway for secretion. Following secretion, ACBP is proteolytically cleaved to the active neuropeptides by protease activity on the surface of astrocytes. Neurosteroids, such as pregnenolone sulfate, were previously shown to modulate the excitatory/inhibitory balance in brain through increased release of glutamate and decreased release of GABA. These effects of steroids in neurons will be reinforced by the release of endozepines from astrocytes shown here, and suggest an orchestrated astrocyte-neuron cross-talk that can affect a broad spectrum of behavioral functions.


Asunto(s)
Astrocitos/metabolismo , Inhibidor de la Unión a Diazepam/química , Inhibidor de la Unión a Diazepam/metabolismo , Hidrocortisona/farmacología , Pregnenolona/farmacología , Animales , Animales Recién Nacidos , Antiinflamatorios/farmacología , Encéfalo/metabolismo , Dictyostelium/metabolismo , Ácido Glutámico/metabolismo , Ratones , Neuroglía/metabolismo , Neuronas/metabolismo , Péptidos/química , Transducción de Señal
10.
Nat Neurosci ; 9(8): 996-8, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16829956

RESUMEN

In addition to their role as chemorepellent netrin-1 receptors, UNC5 proteins may mediate cell death because they induce apoptosis in cultured cells. To test this in vivo, we generated Unc5a (formerly Unc5h1) knockout mice and found that this deletion decreased apoptosis and increased the number of neurons in the spinal cord. In contrast, loss of netrin-1 (Ntn1) did not affect the amount of apoptosis, suggesting that NTN1 is not required for neuronal apoptosis in vivo.


Asunto(s)
Apoptosis/fisiología , Factores de Crecimiento Nervioso/metabolismo , Neuronas/metabolismo , Receptores de Superficie Celular/metabolismo , Médula Espinal/citología , Médula Espinal/embriología , Proteínas Supresoras de Tumor/metabolismo , Animales , Ratones , Ratones Noqueados , Factores de Crecimiento Nervioso/genética , Receptores de Netrina , Netrina-1 , Neuronas/patología , Receptores de Superficie Celular/genética , Médula Espinal/anomalías , Médula Espinal/metabolismo , Proteínas Supresoras de Tumor/genética
11.
J Comp Neurol ; 527(18): 3087-3098, 2019 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-31152449

RESUMEN

Most cognitive and psychiatric disorders are thought to be disorders of the synapse, yet the precise synapse defects remain unknown. Because synapses are highly specialized anatomical structures, defects in synapse formation and function can often be observed as changes in microscale neuroanatomy. Unfortunately, few methods are available for accurate analysis of synaptic structures in human postmortem tissues. Here, we present a methodological pipeline for assessing presynaptic and postsynaptic structures in human postmortem tissue that is accurate, rapid, and relatively inexpensive. Our method uses small tissue blocks from postmortem human brains, immersion fixation, lipophilic dye (DiI) labeling, and confocal microscopy. As proof of principle, we analyzed presynaptic and postsynaptic structures from hippocampi of 13 individuals aged 4 months to 71 years. Our results indicate that postsynaptic CA1 dendritic spine shape and density do not change in adults, while presynaptic DG mossy fiber boutons undergo significant structural rearrangements with normal aging. This suggests that mossy fiber synapses, which play a major role in learning and memory, may remain dynamic throughout life. Importantly, we find that human CA1 spine densities observed using this method on tissue that is up to 28 h postmortem is comparable to prior studies using tissue with much shorter postmortem intervals. Thus, the ease of our protocol and suitability on tissue with longer postmortem intervals should facilitate higher-powered studies of human presynaptic and postsynaptic structures in healthy and diseased states.


Asunto(s)
Hipocampo/química , Hipocampo/patología , Terminales Presinápticos/química , Terminales Presinápticos/patología , Coloración y Etiquetado/métodos , Adulto , Anciano , Autopsia , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Sinapsis/química , Sinapsis/patología , Adulto Joven
12.
J Med Chem ; 50(26): 6607-17, 2007 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-18038971

RESUMEN

Peptidyl-prolyl cis-trans isomerases are a group of cytosolic enzymes initially characterized by their ability to catalyze the cis-trans isomerization of peptidyl-prolyl bonds. This represents a significant event for protein folding because cis-proline introduces critical bends within the protein conformation. FK506-binding proteins (FKBPs) represent one of the three families of enzymes sharing peptidyl-prolyl cis-trans isomerase activity. Inhibitors of FKBP12, in particular, have potent neurotrophic properties both in vivo and in vitro. Here, we describe a fragment-based unbiased nuclear magnetic resonance drug discovery approach for the identification of novel classes of chemical inhibitors against FKBP12. Compared to FK506, the fragment-based FKBP12 inhibitors developed herein possess significant advantages as drug candidates.


Asunto(s)
Morfolinas/síntesis química , Proteína 1A de Unión a Tacrolimus/antagonistas & inhibidores , Animales , Línea Celular , Diseño de Fármacos , Humanos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Morfolinas/química , Morfolinas/farmacología , Neuritas/efectos de los fármacos , Neuritas/fisiología , Ratas , Ratas Long-Evans , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Relación Estructura-Actividad , Tacrolimus/química , Tacrolimus/farmacología , Proteína 1A de Unión a Tacrolimus/química
13.
Curr Opin Neurobiol ; 45: 39-44, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28388510

RESUMEN

For most neurons to function properly, they need to develop synaptic specificity. This requires finding specific partner neurons, building the correct types of synapses, and fine-tuning these synapses in response to neural activity. Synaptic specificity is common at both a neuron's input and output synapses, whereby unique synapses are built depending on the partnering neuron. Neuroscientists have long appreciated the remarkable specificity of neural circuits but identifying molecular mechanisms mediating synaptic specificity has only recently accelerated. Here, we focus on recent progress in understanding input and output synaptic specificity in the mammalian brain. We review newly identified circuit examples for both and the latest research identifying molecular mediators including Kirrel3, FGFs, and DGLα. Lastly, we expect the pace of research on input and output specificity to continue to accelerate with the advent of new technologies in genomics, microscopy, and proteomics.


Asunto(s)
Neuronas/fisiología , Sinapsis/metabolismo , Animales , Humanos , Neuronas/citología , Neuronas/metabolismo , Transducción de Señal/genética
14.
eNeuro ; 4(3)2017.
Artículo en Inglés | MEDLINE | ID: mdl-28670619

RESUMEN

Neural circuits balance excitatory and inhibitory activity and disruptions in this balance are commonly found in neurodevelopmental disorders. Mice lacking the intellectual disability and autism-associated gene Kirrel3 have an excitation-inhibition imbalance in the hippocampus but the precise synaptic changes underlying this functional defect are unknown. Kirrel3 is a homophilic adhesion molecule expressed in dentate gyrus (DG) and GABA neurons. It was suggested that the excitation-inhibition imbalance of hippocampal neurons in Kirrel3 knockout mice is due to loss of mossy fiber (MF) filopodia, which are DG axon protrusions thought to excite GABA neurons and thereby provide feed-forward inhibition to CA3 pyramidal neurons. Fewer filopodial structures were observed in Kirrel3 knockout mice but neither filopodial synapses nor DG en passant synapses, which also excite GABA neurons, were examined. Here, we used serial block-face scanning electron microscopy (SBEM) with 3D reconstruction to define the precise connectivity of MF filopodia and elucidate synaptic changes induced by Kirrel3 loss. Surprisingly, we discovered wildtype MF filopodia do not synapse exclusively onto GABA neurons as previously thought, but instead synapse with similar frequency onto GABA neurons and CA3 neurons. Moreover, Kirrel3 loss selectively reduces MF filopodial synapses onto GABA neurons but not those made onto CA3 neurons or en passant synapses. In sum, the selective loss of MF filopodial synapses with GABA neurons likely underlies the hippocampal activity imbalance observed in Kirrel3 knockout mice and may impact neural function in patients with Kirrel3-dependent neurodevelopmental disorders.


Asunto(s)
Hipocampo/citología , Proteínas de la Membrana/deficiencia , Fibras Musgosas del Hipocampo/ultraestructura , Células Piramidales/metabolismo , Sinapsis/ultraestructura , Animales , Animales Recién Nacidos , Dendritas/genética , Dendritas/metabolismo , Dendritas/ultraestructura , Femenino , Hipocampo/ultraestructura , Imagenología Tridimensional , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Microscopía Electrónica , Células Piramidales/ultraestructura , Sinapsis/genética , Vesículas Sinápticas/genética , Vesículas Sinápticas/ultraestructura , Ácido gamma-Aminobutírico/metabolismo
15.
Neuron ; 96(1): 160-176.e8, 2017 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-28957665

RESUMEN

Hippocampal CA3 neurons form synapses with CA1 neurons in two layers, stratum oriens (SO) and stratum radiatum (SR). Each layer develops unique synaptic properties but molecular mechanisms that mediate these differences are unknown. Here, we show that SO synapses normally have significantly more mushroom spines and higher-magnitude long-term potentiation (LTP) than SR synapses. Further, we discovered that these differences require the Type II classic cadherins, cadherins-6, -9, and -10. Though cadherins typically function via trans-cellular homophilic interactions, our results suggest presynaptic cadherin-9 binds postsynaptic cadherins-6 and -10 to regulate mushroom spine density and high-magnitude LTP in the SO layer. Loss of these cadherins has no effect on the lower-magnitude LTP typically observed in the SR layer, demonstrating that cadherins-6, -9, and -10 are gatekeepers for high-magnitude LTP. Thus, Type II cadherins may uniquely contribute to the specificity and strength of synaptic changes associated with learning and memory.


Asunto(s)
Región CA1 Hipocampal/fisiología , Cadherinas/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Potenciación a Largo Plazo/fisiología , Sinapsis/fisiología , Animales , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/ultraestructura , Cadherinas/metabolismo , Células Cultivadas , Cricetinae , Estimulación Eléctrica , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/fisiología , Neuronas/ultraestructura , Ratas , Sinapsis/ultraestructura
16.
J Neurosci ; 23(36): 11279-88, 2003 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-14672991

RESUMEN

Netrin-1 is a bifunctional guidance cue that directs migrating neurons and axons based on specific receptors expressed on the cell surface. Attraction occurs through the receptor Deleted in Colorectal Cancer (DCC) and repulsion occurs through a receptor complex of DCC and UNC5H, the vertebrate homolog to Caenorhabditis elegans UNC-5, but how the specific surface expression of these receptors is achieved remains unknown. Here, we demonstrate that surface expression of UNC5H1 is regulated in neurons by protein interacting with C kinase-1 (PICK1) and protein kinase C (PKC), and show that one mechanism by which cells control their response to netrin-1 is by changing the surface availability of receptors. We identified PICK1 as a binding partner for UNC5H1 using the yeast two-hybrid system and found that the extreme three C-terminal amino acids of UNC5H1 interact with the PSD-95/Dlg/ZO-1 (PDZ) domain of PICK1. Coexpression of UNC5H1 and PICK1 in heterologous cells results in the recruitment of PICK1 to UNC5H1 clusters. Endogenous UNC5H1 and PICK1 coimmunoprecipitate from extracts of cultured hippocampal neurons and P4 cortices, and immunohistochemistry shows that UNC5H1, PICK1, and PKC are all present in growth cones. PKC activation induces the formation of UNC5H1/PICK1/PKC complexes and leads to the specific removal of UNC5H1, but not DCC, from the surface of neurons and growth cones via a PICK1/PKC-dependent mechanism. Lastly, we demonstrate that activating PKC, which decreases surface expression of UNC5H1, inhibits netrin-1-dependent collapse of hippocampal growth cones. Together, our results suggest that by regulating the surface expression of UNC5Hs, an axon can modulate its repellent response to netrin-1.


Asunto(s)
Proteínas Portadoras/metabolismo , Membrana Celular/metabolismo , Neuronas/metabolismo , Proteínas Nucleares , Proteína Quinasa C/metabolismo , Receptores de Superficie Celular/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Animales , Sitios de Unión , Células COS , Proteínas Portadoras/análisis , Línea Celular , Membrana Celular/enzimología , Células Cultivadas , Cricetinae , Proteínas del Citoesqueleto , Conos de Crecimiento/química , Conos de Crecimiento/enzimología , Conos de Crecimiento/metabolismo , Hipocampo/citología , Receptores de Netrina , Neuronas/enzimología , Proteína Quinasa C/análisis , Proteína Quinasa C-alfa , Estructura Terciaria de Proteína , Transporte de Proteínas , Ratas , Receptores de Superficie Celular/análisis , Proteínas Recombinantes de Fusión/análisis
17.
Cell Adh Migr ; 9(3): 193-201, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25837840

RESUMEN

During brain development, billions of neurons organize into highly specific circuits. To form specific circuits, neurons must build the appropriate types of synapses with appropriate types of synaptic partners while avoiding incorrect partners in a dense cellular environment. Defining the cellular and molecular rules that govern specific circuit formation has significant scientific and clinical relevance because fine scale connectivity defects are thought to underlie many cognitive and psychiatric disorders. Organizing specific neural circuits is an enormously complicated developmental process that requires the concerted action of many molecules, neural activity, and temporal events. This review focuses on one class of molecules postulated to play an important role in target selection and specific synapse formation: the classic cadherins. Cadherins have a well-established role in epithelial cell adhesion, and although it has long been appreciated that most cadherins are expressed in the brain, their role in synaptic specificity is just beginning to be unraveled. Here, we review past and present studies implicating cadherins as active participants in the formation, function, and dysfunction of specific neural circuits and pose some of the major remaining questions.


Asunto(s)
Cadherinas/fisiología , Neuronas/fisiología , Sinapsis/fisiología , Animales , Adhesión Celular/fisiología , Hipocampo/fisiología , Humanos , Ratones
18.
Elife ; 4: e09395, 2015 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-26575286

RESUMEN

Synaptic target specificity, whereby neurons make distinct types of synapses with different target cells, is critical for brain function, yet the mechanisms driving it are poorly understood. In this study, we demonstrate Kirrel3 regulates target-specific synapse formation at hippocampal mossy fiber (MF) synapses, which connect dentate granule (DG) neurons to both CA3 and GABAergic neurons. Here, we show Kirrel3 is required for formation of MF filopodia; the structures that give rise to DG-GABA synapses and that regulate feed-forward inhibition of CA3 neurons. Consequently, loss of Kirrel3 robustly increases CA3 neuron activity in developing mice. Alterations in the Kirrel3 gene are repeatedly associated with intellectual disabilities, but the role of Kirrel3 at synapses remained largely unknown. Our findings demonstrate that subtle synaptic changes during development impact circuit function and provide the first insight toward understanding the cellular basis of Kirrel3-dependent neurodevelopmental disorders.


Asunto(s)
Hipocampo/fisiología , Proteínas de la Membrana/metabolismo , Fibras Musgosas del Hipocampo/metabolismo , Neuronas/fisiología , Sinapsis/metabolismo , Animales , Línea Celular , Técnicas de Inactivación de Genes , Hipocampo/embriología , Proteínas de la Membrana/deficiencia , Ratones , Ratones Noqueados , Ratas
20.
Neural Dev ; 7: 9, 2012 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-22369234

RESUMEN

BACKGROUND: The assembly of neural circuits requires the concerted action of both genetically determined and activity-dependent mechanisms. Calcium-regulated transcription may link these processes, but the influence of specific transcription factors on the differentiation of synapse-specific properties is poorly understood. Here we characterize the influence of NeuroD2, a calcium-dependent transcription factor, in regulating the structural and functional maturation of the hippocampal mossy fiber (MF) synapse. RESULTS: Using NeuroD2 null mice and in vivo lentivirus-mediated gene knockdown, we demonstrate a critical role for NeuroD2 in the formation of CA3 dendritic spines receiving MF inputs. We also use electrophysiological recordings from CA3 neurons while stimulating MF axons to show that NeuroD2 regulates the differentiation of functional properties at the MF synapse. Finally, we find that NeuroD2 regulates PSD95 expression in hippocampal neurons and that PSD95 loss of function in vivo reproduces CA3 neuron spine defects observed in NeuroD2 null mice. CONCLUSION: These experiments identify NeuroD2 as a key transcription factor that regulates the structural and functional differentiation of MF synapses in vivo.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Espinas Dendríticas/genética , Hipocampo/metabolismo , Fibras Musgosas del Hipocampo/metabolismo , Neuropéptidos/genética , Sinapsis/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Cultivadas , Espinas Dendríticas/metabolismo , Ratones , Ratones Noqueados , Neuronas/metabolismo , Neuropéptidos/metabolismo , Sinapsis/metabolismo
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