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9 publication(s) since Janvier 2010:

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09/01/2018 | Curr Opin Neurobiol   IF 6
Neural circuit dysfunction in mouse models of neurodevelopmental disorders.
Del Pino I, Rico B, Marin O

Neuropsychiatric disorders arise from the alteration of normal brain developmental trajectories disrupting the function of specific neuronal circuits. Recent advances in human genetics have greatly accelerated the identification of genes whose variation increases the susceptibility for neurodevelopmental disorders, most notably for autism spectrum disorder (ASD) and schizophrenia. In parallel, experimental studies in animal models-most typically in mice-are beginning to shed light on the role of these genes in the development and function of specific brain circuits. In spite of their limitations, understanding the impact of pathological gene variation in animal models at the level of specific neuronal populations and circuits will likely contribute to orienting human clinical studies in the search for precise disease mechanisms and novel treatments.

10/04/2017 | Nat Neurosci   IF 21.1
Abnormal wiring of CCK+ basket cells disrupts spatial information coding.
Del Pino I, Brotons-Mas JR, Marques-Smith A, Marighetto A, Frick A, Marin O, Rico B

The function of cortical GABAergic interneurons is largely determined by their integration into specific neural circuits, but the mechanisms controlling the wiring of these cells remain largely unknown. This is particularly true for a major population of basket cells that express the neuropeptide cholecystokinin (CCK). Here we found that the tyrosine kinase receptor ErbB4 was required for the normal integration into cortical circuits of basket cells expressing CCK and vesicular glutamate transporter 3 (VGlut3). The number of inhibitory synapses made by CCK+VGlut3+ basket cells and the inhibitory drive they exerted on pyramidal cells were reduced in conditional mice lacking ErbB4. Developmental disruption of the connectivity of these cells diminished the power of theta oscillations during exploratory behavior, disrupted spatial coding by place cells, and caused selective alterations in spatial learning and memory in adult mice. These results suggest that normal integration of CCK+ basket cells in cortical networks is key to support spatial coding in the hippocampus.

11/09/2015 | Science   IF 41
Tuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch.
Dehorter N, Ciceri G, Bartolini G, Lim L, del Pino I, Marin O

The function of neural circuits depends on the generation of specific classes of neurons. Neural identity is typically established near the time when neurons exit the cell cycle to become postmitotic cells, and it is generally accepted that, once the identity of a neuron has been established, its fate is maintained throughout life. Here, we show that network activity dynamically modulates the properties of fast-spiking (FS) interneurons through the postmitotic expression of the transcriptional regulator Er81. In the adult cortex, Er81 protein levels define a spectrum of FS basket cells with different properties, whose relative proportions are, however, continuously adjusted in response to neuronal activity. Our findings therefore suggest that interneuron properties are malleable in the adult cortex, at least to a certain extent.

29/09/2014 | Dev Cell   IF 9.2
Sculpting circuits: CRH interneurons modulate neuronal integration.
Del Pino I, Marin O

Integration of newly generated neurons into adult cell assemblies is a key mechanism for network plasticity. In this issue of Developmental Cell, Garcia et al. (2014) reveal a neuropeptidergic signaling mechanism by which interneurons of the olfactory system act as directors for the activity-dependent integration of adult-born granule cells.

Glycine receptors (GlyRs) mediate inhibitory neurotransmission in spinal cord and brainstem. They are clustered at inhibitory postsynapses via a tight interaction of their beta subunits (GlyRbeta) with the scaffolding protein gephyrin. In an attempt to isolate additional proteins interacting with GlyRbeta, we performed pulldown experiments with rat brain extracts using a glutathione S-transferase fusion protein encompassing amino acids 378-455 of the large intracellular loop of GlyRbeta as bait. This identified syndapin I (SdpI) as a novel interaction partner of GlyRbeta that coimmunoprecipitates with native GlyRs from brainstem extracts. Both SdpI and SdpII bound efficiently to the intracellular loop of GlyRbeta in vitro and colocalized with GlyRbeta upon coexpression in COS-7 cells. The SdpI-binding site was mapped to a proline-rich sequence of 22 amino acids within the intracellular loop of GlyRbeta. Deletion and point mutation analysis disclosed that SdpI binding to GlyRbeta is Src homology 3 domain-dependent. In cultured rat spinal cord neurons, SdpI immunoreactivity was found to partially colocalize with marker proteins of inhibitory and excitatory synapses. When SdpI was acutely knocked down in cultured spinal cord neurons by viral miRNA expression, postsynaptic GlyR clusters were significantly reduced in both size and number. Similar changes in GlyR cluster properties were found in spinal cultures from SdpI-deficient mice. Our results are consistent with a role of SdpI in the trafficking and/or cytoskeletal anchoring of synaptic GlyRs.

18/09/2013 | Neuron   IF 14.4
Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes.
Del Pino I, Garcia-Frigola C, Dehorter N, Brotons-Mas JR, Alvarez-Salvado E, Martinez de Lagran M, Ciceri G, Gabaldon MV, Moratal D, Dierssen M, Canals S, Marin O, Rico B

Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.

09/2012 | Development   IF 5.8
Focal adhesion kinase regulates actin nucleation and neuronal filopodia formation during axonal growth.
Chacon MR, Navarro AI, Cuesto G, del Pino I, Scott R, Morales M, Rico B

The establishment of neural circuits depends on the ability of axonal growth cones to sense their surrounding environment en route to their target. To achieve this, a coordinated rearrangement of cytoskeleton in response to extracellular cues is essential. Although previous studies have identified different chemotropic and adhesion molecules that influence axonal development, the molecular mechanism by which these signals control the cytoskeleton remains poorly understood. Here, we show that in vivo conditional ablation of the focal adhesion kinase gene (Fak) from mouse hippocampal pyramidal cells impairs axon outgrowth and growth cone morphology during development, which leads to functional defects in neuronal connectivity. Time-lapse recordings and in vitro FRAP analysis indicate that filopodia motility is altered in growth cones lacking FAK, probably owing to deficient actin turnover. We reveal the intracellular pathway that underlies this process and describe how phosphorylation of the actin nucleation-promoting factor N-WASP is required for FAK-dependent filopodia formation. Our study reveals a novel mechanism through which FAK controls filopodia formation and actin nucleation during axonal development.

02/09/2011 | Biochem Biophys Res Commun   IF 2.7
The trafficking proteins Vacuolar Protein Sorting 35 and Neurobeachin interact with the glycine receptor beta-subunit.
del Pino I, Paarmann I, Karas M, Kilimann MW, Betz H

Inhibitory glycine receptors (GlyRs) are densely packed in the postsynaptic membrane due to a high-affinity interaction of their beta-subunits with the scaffolding protein gephyrin. Here, we used an affinity-based proteomic approach to identify the trafficking proteins Vacuolar Protein Sorting 35 (Vps35) and Neurobeachin (Nbea) as novel GlyR beta-subunit (GlyRbeta) interacting proteins in rat brain. Recombinant Vps35 and a central fragment of Nbea bound to the large intracellular loop of GlyRbeta in glutathione-S-transferase pull-downs; in addition, Vps35 displayed binding to gephyrin. Immunocytochemical staining of spinal cord sections revealed Nbea immunoreactivity apposed to and colocalizing with marker proteins of inhibitory synapses. Our data are consistent with roles of Vps35 and Nbea in the retrieval and post-Golgi trafficking of synaptic GlyRs and possibly other neurotransmitter receptors.

20/01/2010 | J Neurosci   IF 6.1
Neuroblastoma phox2b variants stimulate proliferation and dedifferentiation of immature sympathetic neurons.
Reiff T, Tsarovina K, Majdazari A, Schmidt M, del Pino I, Rohrer H

Neuroblastoma is a pediatric tumor that is thought to arise from autonomic precursors in the neural crest. Mutations in the PHOX2B gene have been observed in familial and sporadic forms of neuroblastoma and represent the first defined genetic predisposition for neuroblastoma. Here, we address the mechanisms that may underlie this predisposition, comparing the function of wild-type and mutant Phox2b proteins ectopically expressed in proliferating, embryonic sympathetic neurons. Phox2b displays a strong antiproliferative effect, which is lost in all Phox2b neuroblastoma variants analyzed. In contrast, an increase in sympathetic neuron proliferation is elicited by Phox2b variants with mutations in the homeodomain when endogenous Phox2b levels are lowered by siRNA-mediated knockdown to mimic the situation of heterozygous PHOX2B mutations in neuroblastoma. The increased proliferation is blocked by Hand2 knockdown and the antiproliferative Phox2b effects are rescued by Hand2 overexpression, implying Hand2 in Phox2b-mediated proliferation control. A Phox2b variant with a nonsense mutation in the homeodomain elicits, in addition, a decreased expression of characteristic marker genes. Together, these results suggest that PHOX2B mutations predispose to neuroblastoma by increasing proliferation and promoting dedifferentiation of cells in the sympathoadrenergic lineage.