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1.
Mol Psychiatry ; 21(12): 1740-1751, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27457814

RESUMO

SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75NTR, required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75NTR was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2-/- mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75NTR and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.


Assuntos
Receptores de Superfície Celular/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Camundongos , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Receptor trkB/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Acta Neuropathol Commun ; 7(1): 30, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823891

RESUMO

TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.


Assuntos
Senescência Celular/fisiologia , Desenvolvimento Muscular/fisiologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mioblastos/patologia , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/metabolismo , Mioblastos/metabolismo , Linhagem , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
3.
Neuroscience ; 140(4): 1223-37, 2006 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-16631312

RESUMO

The temporal sequence of changes in electrophysiological properties during postnatal development in different neuronal populations has been the subject of previous studies. Those studies demonstrated major physiological modifications with age, and postnatal periods in which such changes are more pronounced. Until now, no similar systematic study has been performed in motoneurons of the oculomotor nucleus. This work has two main aims: first, to determine whether the physiological changes in oculomotor nucleus motoneurons follow a similar time course for different parameters; and second, to compare the temporal sequence with that in other neuronal populations. We recorded the electrophysiological properties of 134 identified oculomotor nucleus motoneurons from 1 to 40 days postnatal in brain slices of rats. The resting membrane potential did not significantly change with postnatal development, and it had a mean value of -61.8 mV. The input resistance and time constant diminished from 82.9-53.1 M omega and from 9.4-4.9 ms respectively with age. These decrements occurred drastically in a short time after birth (1-5 days postnatally). The motoneurons' rheobase gradually decayed from 0.29-0.11 nA along postnatal development. From birth until postnatal day 15 and postnatal day 20 respectively, the action potential shortened from 2.3-1.2 ms, and the medium afterhyperpolarization from 184.8-94.4 ms. The firing gain and the maximum discharge increased with age. The former rose continuously, while the increase in maximum discharge was most pronounced between postnatal day 16 and postnatal day 20. We conclude that the developmental sequence was not similar for all electrophysiological properties, and was unique for each neuronal population.


Assuntos
Potenciais de Ação/fisiologia , Neurônios Motores/fisiologia , Nervo Oculomotor/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Eletrofisiologia , Feminino , Masculino , Ratos , Ratos Wistar , Fatores de Tempo
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