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1.
Zootaxa ; 4657(1): zootaxa.4657.1.13, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31716807

RESUMO

To date, 26 species of Theloderma have been described and all are distributed throughout Southeast Asia from Assam in northeastern India to Myanmar, Indochina, the Malay Peninsula, and the islands of the Greater Sundas: Sumatra and Borneo (Frost 2019). The tadpoles of only 12 species have been described and published: T. asperum (Boulenger); T. auratum Poyarkov, Kropachev, Gogoleva Orlov; T. bicolor (Bourret); T. corticale (Boulenger); T. gordoni Taylor; T. horridum (Boulenger); T. leave (Smith); T. moloch (Annandale); T. nebulosum Rowley, Le, Hoang, Dau Cao; T. palliatum Rowley, Le, Hoang, Dau Cao; T. stellatum Taylor; T. vietnamense Poyarkov, Orlov, Moiseeva, Pawangkhanant, Ruangsuwan, Vassilieva, Galoyan, Nguyen Gogoleva (Boulenger 1903; Annandale 1912; Wassersug et al. 1981; Inger et al. 1999; Leong Lim 2003; Inthara et al. 2005; Rowley et al. 2011; Gawor et al. 2012; Orlov et al. 2012; Poyarkov et al. 2015; Kropachev et al. 2018).


Assuntos
Anuros , Fibras Musgosas Hipocampais , Animais , Ásia Sudeste , Bornéu , Índia , Indochina , Indonésia , Larva , Malásia , Mianmar , Filogenia , Vietnã
2.
Mol Med Rep ; 19(4): 3255-3262, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816469

RESUMO

Repulsive guidance molecule a (RGMa) is a membrane­associated glycoprotein that regulates axonal guidance and inhibits axon outgrowth. In our previous study, we hypothesized that RGMa may be involved in temporal lobe epilepsy (TLE) via the repulsive guidance molecule a (RGMa)­focal adhesion kinase (FAK)­Ras signaling pathway. To investigate the role of RGMa in epilepsy, recombinant RGMa protein and FAK inhibitor 14 was intracerebroventricularly injected into a pentylenetetrazol (PTZ) kindling model and Timm staining, co­immunoprecipitation and western blotting analyses were subsequently performed. The results of the present study revealed that intracerebroventricular injection of recombinant RGMa protein reduced the phosphorylation of FAK (Tyr397) and intracerebroventricular injection of FAK inhibitor 14 reduced the interaction between FAK and p120GAP, as wells as Ras expression. Recombinant RGMa protein and FAK inhibitor 14 exerted seizure­suppressant effects; however, recombinant RGMa protein but not FAK inhibitor 14 suppressed mossy fiber sprouting in the PTZ kindling model. Collectively, these results demonstrated that RGMa may be considered as a potential therapeutic agent for epilepsy, and that RGMa may exert the aforementioned biological effects partly via the FAK­p120GAP­Ras signaling pathway.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Glicoproteínas de Membrana/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Convulsões/metabolismo , Convulsões/fisiopatologia , Transdução de Sinais , Proteína p120 Ativadora de GTPase/metabolismo , Proteínas ras/metabolismo , Animais , Modelos Animais de Doenças , Proteínas Ligadas por GPI , Expressão Gênica , Masculino , Glicoproteínas de Membrana/administração & dosagem , Fibras Musgosas Hipocampais/fisiopatologia , Proteínas do Tecido Nervoso/administração & dosagem , Pentilenotetrazol/efeitos adversos , Fosforilação , Ligação Proteica , Ratos , Proteínas Recombinantes , Convulsões/tratamento farmacológico , Convulsões/etiologia , Transdução de Sinais/efeitos dos fármacos , Proteínas ras/genética
3.
Mol Neurobiol ; 56(7): 5025-5031, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30448889

RESUMO

Axonal sprouting is recognized to be an important mean of repair after neurologic injury. Some characteristic aftermaths of pilocarpine-induced status epilepticus (SE) in the immature rat are nerve cell loss and rearrangement of neuronal fibers. SE induced cell degeneration exclusively in the hippocampal CA1 subfield. Development of neuronal death becomes evident within hours after SE, following a delayed time course ranging from 6 to 48 h post-SE. An incidental finding is that pilocarpine induces within 48 h an aberrant growth of hippocampal mossy fibers in the hippocampus, especially in the infrapyramidal region of the CA3-subfield. We found a strong infrapyramidal band of mossy fibers along the entire stratum oriens of the CA3-region. No mossy fibers sprouting into the inner molecular layer of the dentate gyrus, or CA1 sprouting into the stratum moleculare of CA1 were noted. Signs of aberrant connectivity were found in six of the 10 pilocarpine-treated animals. This study provides the demonstration that pilocarpine within 48 h consistently results in the formation of ectopic hippocampal mossy fibers in a 2-week-old pup. This indicates a high degree of axonal reorganization in the hippocampus. It remains controversial whether such reorganization is the cause or consequence of chronic seizures. We assume that these additional infrapyramidal mossy fibers may influence the way in which granule cells drive pyramidal cells in CA3.


Assuntos
Fibras Musgosas Hipocampais/química , Fibras Musgosas Hipocampais/crescimento & desenvolvimento , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Estado Epiléptico/patologia , Animais , Animais Recém-Nascidos , Feminino , Masculino , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Pilocarpina/toxicidade , Ratos , Ratos Wistar , Estado Epiléptico/induzido quimicamente
4.
J Neurosci ; 39(1): 28-43, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389838

RESUMO

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 Fmr1 knock-out (KO) mice. We observed a reduction of voltage-independent small conductance calcium (Ca2+)-activated K+ (SK) currents in both male and female mice, leading to decreased action potential (AP) threshold and reduced medium afterhyperpolarization. These SK-channel-dependent deficits led to markedly increased AP firing and abnormal input-output signal transmission of CA3 pyramidal neurons. The SK-current defect was mediated, at least in part, by loss of FMRP interaction with the SK channels (specifically the SK2 isoform), without changes in channel expression. Intracellular application of selective SK-channel openers or a genetic reintroduction of an N-terminal FMRP fragment lacking the ability to associate with polyribosomes normalized all observed excitability defects in CA3 pyramidal neurons of Fmr1 KO mice. These results suggest that dysfunction of voltage-independent SK channels is the primary cause of CA3 neuronal hyperexcitability in Fmr1 KO mice and support the critical translation-independent role for the fragile X mental retardation protein as a regulator of neural excitability. Our findings may thus provide a new avenue to ameliorate hippocampal excitability defects in FXS.SIGNIFICANCE STATEMENT Despite two decades of research, no effective treatment is currently available for fragile X syndrome (FXS). Neuronal hyperexcitability is widely considered one of the hallmarks of FXS. Excitability research in the FXS field has thus far focused primarily on voltage-gated ion channels, while contributions from voltage-independent channels have been largely overlooked. Here we report that voltage-independent small conductance calcium-activated potassium (SK)-channel dysfunction causes hippocampal neuron hyperexcitability in the FXS mouse model. Our results support the idea that translation-independent function of fragile X mental retardation protein has a major role in regulating ion-channel activity, specifically the SK channels, in hyperexcitability defects in FXS. Our findings may thus open a new direction to ameliorate hippocampal excitability defects in FXS.


Assuntos
Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Potenciais de Ação/fisiologia , Animais , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/fisiologia , Feminino , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Musgosas Hipocampais/fisiologia , Células Piramidais/fisiologia , Receptores de Ácido Caínico/genética , Receptores de Ácido Caínico/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/agonistas , Transmissão Sináptica/fisiologia
5.
J Clin Invest ; 129(1): 163-168, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30352049

RESUMO

Angelman syndrome (AS) is a neurodevelopmental disorder in which epilepsy is common (~90%) and often refractory to antiepileptics. AS is caused by mutation of the maternal allele encoding the ubiquitin protein ligase E3A (UBE3A), but it is unclear how this genetic insult confers vulnerability to seizure development and progression (i.e., epileptogenesis). Here, we implemented the flurothyl kindling and retest paradigm in AS model mice to assess epileptogenesis and to gain mechanistic insights owed to loss of maternal Ube3a. AS model mice kindled similarly to wild-type mice, but they displayed a markedly increased sensitivity to flurothyl-, kainic acid-, and hyperthermia-induced seizures measured a month later during retest. Pathological characterization revealed enhanced deposition of perineuronal nets in the dentate gyrus of the hippocampus of AS mice in the absence of overt neuronal loss or mossy fiber sprouting. This pro-epileptogenic phenotype resulted from Ube3a deletion in GABAergic but not glutamatergic neurons, and it was rescued by pancellular reinstatement of Ube3a at postnatal day 21 (P21), but not during adulthood. Our results suggest that epileptogenic susceptibility in AS patients is a consequence of the dysfunctional development of GABAergic circuits, which may be amenable to therapies leveraging juvenile reinstatement of UBE3A.


Assuntos
Síndrome de Angelman , Fibras Musgosas Hipocampais , Convulsões , Ubiquitina-Proteína Ligases , Síndrome de Angelman/genética , Síndrome de Angelman/metabolismo , Síndrome de Angelman/patologia , Síndrome de Angelman/terapia , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Fibras Musgosas Hipocampais/metabolismo , Fibras Musgosas Hipocampais/patologia , Convulsões/genética , Convulsões/metabolismo , Convulsões/patologia , Convulsões/terapia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
6.
Biochem Biophys Res Commun ; 508(4): 1082-1087, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30553452

RESUMO

B23, also known as nucleophosmin (NPM), is multifunctional protein directly implicated in cell proliferation, cell cycle progression, and cell survival. In the current study, in addition to confirming its anti-apoptotic function in neuronal survival, we demonstrated that the spatial-temporal expression profile of B23 during development of hippocampal neurons is high in the embryonic stage, down-regulated after birth, and preferentially localized at the tips of growing neuritis and branching points. Overexpression of B23 promotes axon growth with abundant branching points in growing hippocampal neurons, but depletion of B23 impairs axon growth, leading to neuronal death. Following injury to the trisynaptic path in hippocampal slice, overexpression of B23 remarkably increased the number and length of regenerative fibers in the mossy fiber path. Our study suggests that B23 expression in developing neurons is essential for neuritogenesis and axon growth and that up-regulation of B23 may be a strategy for enhancing the reconstitution of synaptic paths after injury to hippocampal synapses.


Assuntos
Hipocampo/lesões , Hipocampo/metabolismo , Proteínas Nucleares/metabolismo , Sinapses/metabolismo , Animais , Axônios/metabolismo , Morte Celular , Camundongos , Fibras Musgosas Hipocampais/metabolismo , Fibras Musgosas Hipocampais/patologia , Regeneração Nervosa , Ratos
7.
Cell Rep ; 25(10): 2704-2715.e4, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30517859

RESUMO

The supramammillary nucleus (SuM) of the hypothalamus projects to the dentate gyrus (DG) and the CA2 region of the hippocampus. Although the SuM-to-hippocampus circuits have been implicated in spatial and emotional memory formation, little is known about precise neural connections between the SuM and hippocampus. Here, we report that axons of SuM neurons make monosynaptic connections to granule cells (GCs) and GABAergic interneurons, but not to hilar mossy cells, in the DG and co-release glutamate and γ-aminobutyric acid (GABA) at these synapses. Although inputs from the SuM can excite some interneurons, the inputs alone fail to generate spikes in GCs. However, despite the insufficient excitatory drive and GABAergic co-transmission, SuM inputs have net excitatory effects on GCs and can potentiate GC firing when temporally associated with perforant path inputs. Our results indicate that the SuM influences DG information processing by modulating GC outputs.


Assuntos
Vias Aferentes/fisiologia , Giro Denteado/citologia , Giro Denteado/metabolismo , Ácido Glutâmico/metabolismo , Hipotálamo Posterior/fisiologia , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/fisiologia , Animais , Interneurônios/fisiologia , Camundongos Endogâmicos C57BL , Fibras Musgosas Hipocampais/fisiologia , Optogenética , Via Perfurante/fisiologia , Sinapses/metabolismo
8.
Development ; 145(24)2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30470704

RESUMO

Hindbrain precerebellar neurons arise from progenitor pools at the dorsal edge of the embryonic hindbrain: the caudal rhombic lip. These neurons follow distinct migratory routes to establish nuclei that provide climbing or mossy fiber inputs to the cerebellum. Gli3, a zinc-finger transcription factor in the Sonic hedgehog signaling pathway, is an important regulator of dorsal brain development. We demonstrate that in Gli3-null mutant mice, disrupted neuronal migratory streams lead to a disorganization of precerebellar nuclei. Precerebellar progenitors are properly established in Gli3-null embryos and, using conditional gene inactivation, we provide evidence that Gli3 does not play a cell-autonomous role in migrating precerebellar neurons. Thus, GLI3 likely regulates the development of other hindbrain structures, such as non-precerebellar nuclei or cranial ganglia and their respective projections, which may in turn influence precerebellar migration. Although the organization of non-precerebellar hindbrain nuclei appears to be largely unaffected in absence of Gli3, trigeminal ganglia and their central descending tracts are disrupted. We show that rostrally migrating precerebellar neurons are normally in close contact with these tracts, but are detached in Gli3-null embryos.


Assuntos
Movimento Celular , Cerebelo/citologia , Neurônios/citologia , Neurônios/metabolismo , Proteína Gli3 com Dedos de Zinco/metabolismo , Animais , Núcleo Celular/metabolismo , Embrião de Mamíferos/citologia , Camundongos , Fibras Musgosas Hipocampais/metabolismo , Mutação/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Receptores de Superfície Celular/metabolismo , Rombencéfalo/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Nervo Trigêmeo/citologia , Nervo Trigêmeo/metabolismo
9.
Neuropsychopharmacol Rep ; 38(4): 197-203, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30280523

RESUMO

AIM: The identification of 7,8-dihydroxyflavone (DHF) as a small molecule agonist for tropomyosin-related kinase B (TrkB) facilitated understanding of the role of TrkB signaling in regulating higher brain functions. DHF can penetrate the blood-brain barrier after systemic administration and changes the performance of cognitive and emotional behavioral tasks. However, it is poorly understood how DHF modulates neuronal functions at cellular levels. Aiming to understand the cellular basis underlying DHF-induced modifications of the brain functions, we examined the effects of DHF on the hippocampal excitatory synaptic transmission. METHODS: Field excitatory postsynaptic potentials were recorded using hippocampal slices prepared from adult male mice. Effects of bath-applied DHF on the synaptic efficacy were examined. RESULTS: We found that DHF induced robust synaptic potentiation at the mossy fiber to CA3 synapse. DHF had minimal effects at other hippocampal excitatory synapses or at immature mossy fiber synapse in juvenile mice. The TrkB receptor blockers K252a and ANA-12 did not affect the DHF-induced synaptic potentiation. Drug screening revealed that relatively low concentrations of 2-aminoethoxydiphenylborane blocked the DHF-induced synaptic potentiation. CONCLUSION: Our results demonstrate that DHF selectively potentiates hippocampal mossy fiber synaptic transmission via a TrkB receptor-independent mechanism. This novel neuromodulatory effect of DHF may influence higher brain functions by itself or together with the activation of the TrkB receptor. The rapid induction of the potentiation implies its potential importance in the acute behavioral effects of DHF.


Assuntos
Região CA3 Hipocampal/fisiologia , Potenciais Pós-Sinápticos Excitadores , Flavonas/farmacologia , Fibras Musgosas Hipocampais/fisiologia , Animais , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musgosas Hipocampais/efeitos dos fármacos , Fibras Musgosas Hipocampais/metabolismo , Receptor trkB/agonistas
10.
Neuron ; 100(1): 201-215.e9, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30290982

RESUMO

Pyramidal neuron dendrites integrate synaptic input from multiple partners. Different inputs converging on the same dendrite have distinct structural and functional features, but the molecular mechanisms organizing input-specific properties are poorly understood. We identify the orphan receptor GPR158 as a binding partner for the heparan sulfate proteoglycan (HSPG) glypican 4 (GPC4). GPC4 is enriched on hippocampal granule cell axons (mossy fibers), whereas postsynaptic GPR158 is restricted to the proximal segment of CA3 apical dendrites receiving mossy fiber input. GPR158-induced presynaptic differentiation in contacting axons requires cell-surface GPC4 and the co-receptor LAR. Loss of GPR158 increases mossy fiber synapse density but disrupts bouton morphology, impairs ultrastructural organization of active zone and postsynaptic density, and reduces synaptic strength of this connection, while adjacent inputs on the same dendrite are unaffected. Our work identifies an input-specific HSPG-GPR158 interaction that selectively organizes synaptic architecture and function of developing mossy fiber-CA3 synapses in the hippocampus.


Assuntos
Região CA3 Hipocampal/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Sinapses/metabolismo , Animais , Região CA3 Hipocampal/embriologia , Células HEK293 , Humanos , Camundongos , Fibras Musgosas Hipocampais/embriologia , Neurogênese/fisiologia , Células Piramidais/metabolismo , Ratos , Ratos Long-Evans , Transmissão Sináptica/fisiologia
11.
Radiología (Madr., Ed. impr.) ; 60(5): 404-412, sept.-oct. 2018. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-175301

RESUMO

Objetivo: Evaluar las subestructuras hipocampales utilizando resonancia magnética en pacientes con esclerosis hipocampal (EH), comparando los resultados con el análisis morfológico y la volumetría global del hipocampo. Método: Se incluyeron 25 controles y 25 pacientes con EH, cuyo diagnóstico fue extraído del informe de la junta institucional de epilepsia. Se utilizó FreeSurfer para el procesamiento de los estudios y la obtención de los datos volumétricos. El volumen fue valorado de manera global y por subestructura: fimbria, subiculum, presubiculum, fisura hipocampal, CA1, CA2-CA3, CA4 y giro dentado (GD). Se consideró p <0,05 como estadísticamente significativo. Resultados: Se observó una disminución estadísticamente significativa en el hipocampo homolateral al foco epileptógeno en 19 de los 25 casos (76,0%). A excepción de la fisura hipocampal, se observó una disminución en todas las subestructuras hipocampales homolaterales en la EH derecha (CA1, p = 0,0223; CA2-CA3, p = 0,0066; CA4-GD, p = 0,0066; fimbria, p = 0,0046; presubiculum, p = 0,0087; subiculum, p = 0,0017) y la EH izquierda (CA1, p <0,0001; CA2-CA3, p <0,0001; CA4-GD, p <0,0001; fimbria, p = 0,0183; presubiculum, p <0,0001; subiculum, p <0,0001). En cuatro casos de EH izquierda, ninguna de las subestructuras presentó alteración estadísticamente significativa; sin embargo, se observó una tendencia de atrofia, principalmente en CA2-CA3 y CA4-GD. Conclusión: Los hallazgos sugieren la utilidad de la evaluación de las subestructuras hipocampales para mejorar el desempeño de la imagen en el diagnóstico de la EH


Objective: The pathological classification of hippocampal sclerosis is based on the loss of neurons in the substructures of the hippocampus. This study aimed to evaluate these substructures in patients with hippocampal sclerosis by magnetic resonance imaging and to compare the usefulness of this morphological analysis compared to that of volumetric analysis of the entire hippocampus. Material and methods: We included 25 controls and 25 patients with hippocampal sclerosis whose diagnosis was extracted from the institutional epilepsy board. We used FreeSurfer to process the studies and obtain the volumetric data. We evaluated overall volume and volume by substructure: fimbria, subiculum, presubiculum, hippocampal sulcus, CA1, CA2–CA3, CA4, and dentate gyrus (DG). We considered p < 0.05 statistically significant. Results: We observed statistically significant decreases in the volume of the hippocampus ipsilateral to the epileptogenic focus in 19 (76.0%) of the 25 cases. With the exception of the hippocampal sulcus, we observed a decrease in all ipsilateral hippocampal substructures in patients with right hippocampal sclerosis (CA1, p=0.0223; CA2–CA3, p=0.0066; CA4–GD, p=0.0066; fimbria, p=0.0046; presubiculum, p=0.0087; subiculum, p=0.0017) and in those with left hippocampal sclerosis (CA1, p<0.0001; CA2–CA3, p<0. 0001; CA4–GD, p<0. 0001; fimbria, p=0.0183; presubiculum, p<0. 0001; subiculum, p<0. 0001). In four patients with left hippocampal sclerosis, none of the substructures had statistically significant alterations, although a trend toward atrophy was observed, mainly in CA2–CA3 and CA4–GD. Conclusion: The findings suggest that it can be useful to assess the substructures of the hippocampus to improve the performance of diagnostic imaging in patients with hippocampal sclerosis


Assuntos
Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Hipocampo/ultraestrutura , Esclerose/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Estudos de Casos e Controles , Fibras Musgosas Hipocampais/ultraestrutura , Giro Para-Hipocampal/ultraestrutura , Imagem por Ressonância Magnética/métodos , Estudos Retrospectivos
12.
Neuroreport ; 29(16): 1384-1390, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30169428

RESUMO

Mossy fiber sprouting (MFS) and neuronal loss are important pathological features of chronic epilepsy closely related to the development of spontaneous recurrent seizures. However, the pathological mechanism of MFS remains unclear. Collapsin response mediator protein 2 (CRMP2) is a cytoplasmic protein highly expressed in the nervous system and is involved in axon/dendrite specification and axonal growth. It is possibly associated with the development of MFS. Lacosamide (LCM), a novel antiepileptic drug, was recently found to inhibit the CRMP2-mediated neurite outgrowth. Therefore, we studied the relationships between LCM, CRMP2, and MFS, seeking potential therapeutic targets for epileptogenesis and a better understanding of the mechanism of action of LCM. We used kainic acid to induce status epilepticus in an animal model and examined the resultant changes in protein expression by Western blot and changes in histology by specific staining for cell death and MFS. Our results showed that the expression level of CRMP2 was elevated and the expression level of phosphorylated CRMP2 (p-CRMP2) was reduced following status epilepticus. Administration of LCM not only reversed this effect but also suppressed spontaneous recurrent seizures and reduced MFS and loss of hippocampal neurons. This study reveals that, in addition to its antiseizure efficacy, LCM has a neuroprotective effect and inhibits the development of epilepsy. CRMP2 is possibly involved in the mechanism by which LCM suppresses MFS and is expected to be a new therapeutic target for treating epileptogenesis.


Assuntos
Anticonvulsivantes/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lacosamida/uso terapêutico , Fibras Musgosas Hipocampais/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologia , Animais , Modelos Animais de Doenças , Fluoresceínas/metabolismo , Ácido Caínico/toxicidade , Masculino , Camundongos , Ratos Wistar , Estado Epiléptico/induzido quimicamente , Fatores de Tempo
13.
J Cell Biol ; 217(11): 4007-4024, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185604

RESUMO

Neuronal connections are initiated by axon targeting to form synapses. However, how the maturation of axon terminals is modulated through interacting with postsynaptic elements remains elusive. In this study, we find that ligand of Numb protein X 1 (Lnx1), a postsynaptic PDZ protein expressed in hippocampal CA3 pyramidal neurons, is essential for mossy fiber (MF) axon targeting during the postnatal period. Lnx1 deletion causes defective synaptic arrangement that leads to aberrant presynaptic terminals. We further identify EphB receptors as novel Lnx1-binding proteins to form a multiprotein complex that is stabilized on the CA3 neuron membrane through preventing proteasome activity. EphB1 and EphB2 are independently required to transduce distinct signals controlling MF pruning and targeting for precise DG-CA3 synapse formation. Furthermore, constitutively active EphB2 kinase rescues structure of the wired MF terminals in Lnx1 mutant mice. Our data thus define a retrograde trans-synaptic regulation required for integration of post- and presynaptic structure that participates in building hippocampal neural circuits during the adolescence period.


Assuntos
Axônios/metabolismo , Região CA3 Hipocampal/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Células Piramidais/metabolismo , Sinapses/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Camundongos , Camundongos Knockout , Terminações Pré-Sinápticas/metabolismo , Receptor EphB1/genética , Receptor EphB1/metabolismo , Receptor EphB2/genética , Receptor EphB2/metabolismo , Sinapses/genética , Ubiquitina-Proteína Ligases/genética
14.
eNeuro ; 5(4)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30225345

RESUMO

Action potentials propagating along axons are often followed by prolonged afterdepolarization (ADP) lasting for several tens of milliseconds. Axonal ADP is thought to be an important factor in modulating the fidelity of spike propagation during repetitive firings. However, the mechanism as well as the functional significance of axonal ADP remain unclear, partly due to inaccessibility to small structures of axon for direct electrophysiological recordings. Here, we examined the ionic and electrical mechanisms underlying axonal ADP using whole-bouton recording from mossy fiber terminals in mice hippocampal slices. ADP following axonal action potentials was strongly enhanced by focal application of veratridine, an inhibitor of Na+ channel inactivation. In contrast, tetrodotoxin (TTX) partly suppressed ADP, suggesting that a Na+ channel-dependent component is involved in axonal ADP. The remaining TTX-resistant Na+ channel-independent component represents slow capacitive discharge reflecting the shape and electrical properties of the axonal membrane. We also addressed the functional impact of axonal ADP on presynaptic function. In paired-pulse stimuli, we found that axonal ADP minimally affected the peak height of subsequent action potentials, although the rising phase of action potentials was slightly slowed, possibly due to steady-state inactivation of Na+ channels by prolonged depolarization. Voltage clamp analysis of Ca2+ current elicited by action potential waveform commands revealed that axonal ADP assists short-term facilitation of Ca2+ entry into the presynaptic terminals. Taken together, these data show that axonal ADP maintains reliable firing during repetitive stimuli and plays important roles in the fine-tuning of short-term plasticity of transmitter release by modulating Ca2+ entry into presynaptic terminals.


Assuntos
Potenciais de Ação/fisiologia , Sinalização do Cálcio/fisiologia , Moduladores de Transporte de Membrana/farmacologia , Fibras Musgosas Hipocampais/fisiologia , Canais de Sódio/efeitos dos fármacos , Veratridina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musgosas Hipocampais/efeitos dos fármacos
15.
eNeuro ; 5(4)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30131968

RESUMO

Here we describe a novel mouse model of temporal lobe epilepsy (TLE) that moves the site of kainate injection from the rodent dorsal hippocampus (corresponding to the human posterior hippocampus) to the ventral hippocampus (corresponding to the human anterior hippocampus). We compare the phenotypes of this new model-with respect to seizures, cognitive impairment, affective deficits, and histopathology-to the standard dorsal intrahippocampal kainate model. Our results demonstrate that histopathological measures of granule cell dispersion and mossy fiber sprouting maximize near the site of kainate injection. Somewhat surprisingly, both the dorsal and ventral models exhibit similar spatial memory impairments in addition to similar electrographic and behavioral seizure burdens. In contrast, we find a more pronounced affective (anhedonic) phenotype specifically in the ventral model. These results demonstrate that the ventral intrahippocampal kainic acid model recapitulates critical pathologies of the dorsal model while providing a means to further study affective phenotypes such as depression in TLE.


Assuntos
Anedonia , Ansiedade , Comportamento Animal , Disfunção Cognitiva , Modelos Animais de Doenças , Epilepsia do Lobo Temporal , Agonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Ácido Caínico/farmacologia , Anedonia/efeitos dos fármacos , Anedonia/fisiologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/etiologia , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Giro Denteado/efeitos dos fármacos , Eletroencefalografia , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/fisiopatologia , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Humanos , Ácido Caínico/administração & dosagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musgosas Hipocampais/efeitos dos fármacos
16.
Neuron ; 99(3): 425-427, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-30092210

RESUMO

The pathways that convert neural stem cells (NSCs) into functional neurons in the adult hippocampus are tightly regulated. In this issue of Neuron, Yeh et al. (2018) demonstrate that the activity of dentate mossy cells determines the balance between quiescence and activation of NSCs.


Assuntos
Células-Tronco Adultas , Células-Tronco Neurais , Adulto , Diferenciação Celular , Hipocampo , Humanos , Fibras Musgosas Hipocampais , Neurogênese
17.
eNeuro ; 5(4)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30090852

RESUMO

Tissue plasminogen activator (tPA) is an immediate-early gene important for regulating physiological processes like synaptic plasticity and neurovascular coupling. It has also been implicated in several pathological processes including blood-brain barrier (BBB) permeability, seizure progression, and stroke. These varied reports suggest that tPA is a pleiotropic mediator whose actions are highly compartmentalized in space and time. The specific localization of tPA, therefore, can provide useful information about its function. Accordingly, the goal of this study was to provide a detailed characterization of tPA's regional, cellular, and subcellular localization in the brain. To achieve this, two new transgenic mouse lines were utilized: (1) a PlatßGAL reporter mouse, which houses the ß-galactosidase gene in the tPA locus and (2) a tPABAC-Cerulean mouse, which has a cerulean-fluorescent protein fused in-frame to the tPA C-terminus. Using these two transgenic reporters, we show that while tPA is expressed throughout most regions of the adult murine brain, it appears to be preferentially targeted to fiber tracts in the limbic system. In the hippocampus, confocal microscopy revealed tPA-Cerulean (tPA-Cer) puncta localized to giant mossy fiber boutons (MFBs) and astrocytes in stratum lucidum. With amplification of the tPA-Cer signal, somatically localized tPA was also observed in the stratum oriens (SO)/alveus layer of both CA1 and CA3 subfields. Coimmunostaining of tPA-Cer and interneuronal markers indicates that these tPA-positive cell bodies belong to a subclass of somatostatin (SST)/oriens-lacunosum moleculare (O-LM) interneurons. Together, these data imply that tPA's localization is differentially regulated, suggesting that its neuromodulatory effects may be compartmentalized and specialized to cell type.


Assuntos
Astrócitos/metabolismo , Região CA1 Hipocampal/metabolismo , Região CA3 Hipocampal/metabolismo , Expressão Gênica/fisiologia , Interneurônios/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Transporte Proteico/fisiologia , Somatostatina/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Animais , Região CA1 Hipocampal/diagnóstico por imagem , Região CA3 Hipocampal/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal
18.
Biochem Biophys Res Commun ; 503(4): 2312-2318, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-29964011

RESUMO

Mossy fiber sprouting (MFS) is a pathological phenomenon that is commonly observed in epilepsy, and plentiful data reveal that abnormal phosphorylated modification of tau protein plays a critical role in MSF by the regulation of microtubule dynamics and axonal transport. Ubiquitin C-terminal hydrolase L1 (UCH-L1), a proteasomal deubiquitinating enzyme, has been proved to be associated with tau aggregation through mediating degradation of ubiquitinated and hyperphosphorylated tau. Thus, this study aimed to determine the expression of UCH-L1 in the rat hippocampus during the pentylenetetrazole (PTZ)-induced process and to demonstrate the possible correlation with MFS in epileptogenesis. Seizures were established by intraperitoneal injection of PTZ and LDN-57444 was used to inhibit the hydrolase activity of UCH-L1. We used western blot, immunofluorescence, immunoprecipitation, and timm staining to detect phosphorylated modification of tau and MSF. The results presented that LDN-57444 induced the deteriorated severity of seizures, increased phosphorylation of tau and increased distribution of Timm granules in both the supragranular region of the dentate gyrus (DG) and the stratum pyramidale of CA3 subfield. Our results suggest that UCH-L1 may be associated with hippocampal MSF followed the epileptogenesis through mediating phosphorylation of tau. UCH-L1 may be a potential and novel therapeutic target to limit epileptogenesis.


Assuntos
Excitação Neurológica/fisiologia , Fibras Musgosas Hipocampais/ultraestrutura , Pentilenotetrazol/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Animais , Epilepsia/induzido quimicamente , Fosforilação , Ratos , Proteínas tau/metabolismo
19.
Neuron ; 99(3): 493-510.e4, 2018 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-30057205

RESUMO

Mossy cells (MCs) represent a major population of excitatory neurons in the adult dentate gyrus, a brain region where new neurons are generated from radial neural stem cells (rNSCs) throughout life. Little is known about the role of MCs in regulating rNSCs. Here we demonstrate that MC commissural projections structurally and functionally interact with rNSCs through both the direct glutamatergic MC-rNSC pathway and the indirect GABAergic MC-local interneuron-rNSC pathway. Specifically, moderate MC activation increases rNSC quiescence through the dominant indirect pathway, while high MC activation increases rNSC activation through the dominant direct pathway. In contrast, MC inhibition or ablation leads to a transient increase of rNSC activation, but rNSC depletion only occurs after chronic ablation of MCs. Together, our study identifies MCs as a critical stem cell niche component that dynamically controls adult NSC quiescence and maintenance under various MC activity states through a balance of direct glutamatergic and indirect GABAergic signaling onto rNSCs.


Assuntos
Fibras Musgosas Hipocampais/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Transdução de Sinais/fisiologia , Fatores Etários , Animais , Feminino , Masculino , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Distribuição Aleatória
20.
Brain Res ; 1701: 28-35, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30025975

RESUMO

BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) has demonstrated antiepileptic efficacy, especially for mesial temporal lobe epilepsy (MTLE). Mossy fiber sprouting (MFS) is involved in the pathogenesis of MTLE, and Sema-3A and GAP-43 are pivotal regulators of MFS. This study investigated the effects of ANT-DBS on MFS and expression levels of Sema-3A and GAP-43 as a possible mechanism for seizure suppression. METHODS: Adult male Sprague-Dawley rats were randomly divided into four groups: (1) control (saline injection), (2) KA (kainic acid injection), (3) KA + Sham-DBS (electrode implantation without stimulation), and (4) KA + DBS (electrode implantation with stimulation). Video electroencephalography (EEG) was used to ensure model establishment and monitor seizure frequency, latency, and severity (Racine stage). Chronic ANT stimulation was conducted for 35 days in the KA + DBS group, and MFS compared to the other groups by quantitative Timm staining. Sema-3A and GAP-43 expression levels in the hippocampal formation were evaluated in all groups with western blot. RESULTS: The latency period was significantly prolonged and spontaneous seizure frequency reduced in the KA + DBS group compared to KA and KA + Sham-DBS groups. Staining scores for MFS in CA3 and dentate gyrus (DG) were significantly lower in the KA + DBS group. The KA + DBS group also exhibited decreased GAP-43 expression and increased Sema-3A expression compared to KA and KA + Sham-DBS groups. CONCLUSION: These results suggest that ANT-DBS extends the latent period following epileptogenic stimulation by impeding MFS through modulation of GAP-43 and Sema-3A expression.


Assuntos
Núcleos Anteriores do Tálamo/metabolismo , Epilepsia/patologia , Fibras Musgosas Hipocampais/efeitos dos fármacos , Animais , Núcleo Celular/patologia , Estimulação Encefálica Profunda/métodos , Giro Denteado/efeitos dos fármacos , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/patologia , Proteína GAP-43/metabolismo , Proteína GAP-43/fisiologia , Hipocampo/efeitos dos fármacos , Ácido Caínico/farmacologia , Masculino , Fibras Musgosas Hipocampais/patologia , Ratos , Ratos Sprague-Dawley , Convulsões/patologia , Semaforina-3A/metabolismo , Semaforina-3A/fisiologia
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