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1.
Exp Neurol ; 337: 113571, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33340499

RESUMO

This study examined the antiepileptogenic potential of the antiseizure drug (ASD) levetiracetam (LEV) using the in vitro traumatized-slice and in vivo controlled cortical impact (CCI) models of traumatic brain injury (TBI) in rats when administered early after the injury. For the in vitro model, acute coronal slices (400-450 µm) of rat neocortex (P21-32) were injured via a surgical cut that separated the superficial layers from the deeper regions. Persistent stimulus-evoked epileptiform activity developed within 1-2 h after trauma. In randomly selected slices, LEV (500 µM) was bath-applied for 1 h starting immediately or delayed by 30-80 min after injury. Treated and untreated slices were examined for epileptiform activity via intracellular and extracellular recordings. For the in vivo model, rats (P24-32) were subjected to a non-penetrating, focal, CCI injury targeting the neocortex (5.0 mm diameter; 2.0 mm depth). Immediately after injury, rats were given either a single dose of LEV (60-150 mg/kg, i.p.) or the saline vehicle. At 2-3 weeks after the injury, ex vivo cortical slices were examined for epileptiform activity. The results from the traumatized-slice experiments showed that in vitro treatment with LEV within 60 min of injury significantly reduced (> 50%) the proportion of slices that exhibited stimulus-evoked epileptiform activity. LEV treatment also increased the stimulus intensity required to trigger epileptiform bursts in injured slices by 2-4 fold. Consistent with these findings, LEV treatment of CCI-injured rats (n = 15) significantly reduced the proportion of animals that exhibited spontaneous and stimulus-evoked epileptiform bursts in ex vivo cortical slices compared to saline-treated controls (n = 15 rats), and also significantly increased the stimulus intensity required to evoke epileptiform bursts. These results suggest that early administration of LEV has the potential to prevent or reduce posttraumatic epileptogenesis and that there may be a narrow therapeutic window for successful prophylactic intervention.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/fisiopatologia , Córtex Cerebral/fisiopatologia , Epilepsia/prevenção & controle , Epilepsia/fisiopatologia , Levetiracetam/uso terapêutico , Nootrópicos/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/complicações , Córtex Cerebral/lesões , Fenômenos Eletrofisiológicos , Epilepsia/etiologia , Feminino , Masculino , Neocórtex/lesões , Neocórtex/fisiopatologia , Ratos , Ratos Sprague-Dawley , Tempo para o Tratamento
2.
Neurobiol Learn Mem ; 164: 107042, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31326533

RESUMO

Fragile X Syndrome (FXS) is a leading cause of heritable intellectual disability and autism. Humans with FXS show anxiety, sensory hypersensitivity and impaired learning. The mechanisms of learning impairments can be studied in the mouse model of FXS, the Fmr1 KO mouse, using tone-associated fear memory paradigms. Our previous study reported impaired development of parvalbumin (PV) positive interneurons and perineuronal nets (PNN) in the auditory cortex of Fmr1 KO mice. A recent study suggested PNN dynamics in the auditory cortex following tone-shock association is necessary for fear expression. Together these data suggest that abnormal PNN regulation may underlie tone-fear association learning deficits in Fmr1 KO mice. We tested this hypothesis by quantifying PV and PNN expression in the amygdala, hippocampus and auditory cortex of Fmr1 KO mice following fear conditioning. We found impaired tone-associated memory formation in Fmr1 KO mice. This was paralleled by impaired learning-associated regulation of PNNs in the superficial layers of auditory cortex in Fmr1 KO mice. PV cell density decreased in the auditory cortex in response to fear conditioning in both WT and Fmr1 KO mice. Learning-induced increase of PV expression in the CA3 hippocampus was only observed in WT mice. We also found reduced PNN density in the amygdala and auditory cortex of Fmr1 KO mice in all conditions, as well as reduced PNN intensity in CA2 hippocampus. There was a positive correlation between tone-associated memory and PNN density in the amygdala and auditory cortex, consistent with a tone-association deficit. Altogether our studies suggest a link between impaired PV and PNN regulation within specific regions of the fear conditioning circuit and impaired tone memory formation in Fmr1 KO mice.


Assuntos
Tonsila do Cerebelo/fisiologia , Córtex Auditivo/fisiologia , Medo/fisiologia , Proteína do X Frágil da Deficiência Intelectual/fisiologia , Memória/fisiologia , Neurônios/fisiologia , Animais , Condicionamento Clássico , Proteína do X Frágil da Deficiência Intelectual/genética , Interneurônios/fisiologia , Masculino , Camundongos Knockout , Vias Neurais/fisiologia , Parvalbuminas/metabolismo
3.
Cereb Cortex ; 28(11): 3951-3964, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040407

RESUMO

Abnormal sensory responses associated with Fragile X Syndrome (FXS) and autism spectrum disorders include hypersensitivity and impaired habituation to repeated stimuli. Similar sensory deficits are also observed in adult Fmr1 knock-out (KO) mice and are reversed by genetic deletion of Matrix Metalloproteinase-9 (MMP-9) through yet unknown mechanisms. Here we present new evidence that impaired development of parvalbumin (PV)-expressing inhibitory interneurons may underlie hyper-responsiveness in auditory cortex of Fmr1 KO mice via MMP-9-dependent regulation of perineuronal nets (PNNs). First, we found that PV cell development and PNN formation around GABAergic interneurons were impaired in developing auditory cortex of Fmr1 KO mice. Second, MMP-9 levels were elevated in P12-P18 auditory cortex of Fmr1 KO mice and genetic reduction of MMP-9 to WT levels restored the formation of PNNs around PV cells. Third, in vivo single-unit recordings from auditory cortex neurons showed enhanced spontaneous and sound-driven responses in developing Fmr1 KO mice, which were normalized following genetic reduction of MMP-9. These findings indicate that elevated MMP-9 levels contribute to the development of sensory hypersensitivity by influencing formation of PNNs around PV interneurons suggesting MMP-9 as a new therapeutic target to reduce sensory deficits in FXS and potentially other autism spectrum disorders.


Assuntos
Córtex Auditivo/crescimento & desenvolvimento , Proteína do X Frágil da Deficiência Intelectual/fisiologia , Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , Metaloproteinase 9 da Matriz/fisiologia , Rede Nervosa/crescimento & desenvolvimento , Animais , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Masculino , Metaloproteinase 9 da Matriz/genética , Camundongos Knockout , Parvalbuminas/metabolismo
4.
Neuroscience ; 347: 22-35, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-28189613

RESUMO

Synaptic pruning underlies the transition from an immature to an adult CNS through refinements of neuronal circuits. Our recent study indicates that pubertal synaptic pruning is triggered by the inhibition generated by extrasynaptic α4ßδ GABAA receptors (GABARs) which are increased for 10 d on dendritic spines of CA1 pyramidal cells at the onset of puberty (PND 35-44) in the female mouse, suggesting α4ßδ GABARs as a novel target for the regulation of adolescent synaptic pruning. In the present study we used a pharmacological approach to further examine the role of these receptors in altering spine density during puberty of female mice and the impact of these changes on spatial learning, assessed in adulthood. Two drugs were chronically administered during the pubertal period (PND 35-44): the GABA agonist gaboxadol (GBX, 0.1mg/kg, i.p.), to enhance current gated by α4ßδ GABARs and the neurosteroid/stress steroid THP (3α-OH-5ß-pregnan-20-one, 10mg/kg, i.p.) to decrease expression of α4ßδ. Spine density was determined on PND 56 with Golgi staining. Spatial learning and relearning were assessed using the multiple object relocation task and an active place avoidance task on PND 56. Pubertal GBX decreased spine density post-pubertally by 70% (P<0.05), while decreasing α4ßδ expression with THP increased spine density by twofold (P<0.05), in both cases, with greatest effects on the mushroom spines. Adult relearning ability was compromised in both hippocampus-dependent tasks after pubertal administration of either drug. These findings suggest that an optimal spine density produced by α4ßδ GABARs is necessary for optimal cognition in adults.


Assuntos
Envelhecimento , Região CA1 Hipocampal/fisiologia , Espinhas Dendríticas/fisiologia , Plasticidade Neuronal , Receptores de GABA-A/fisiologia , Aprendizagem Espacial/fisiologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Feminino , Agonistas de Receptores de GABA-A/administração & dosagem , Isoxazóis/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Pregnanolona/administração & dosagem , Receptores de GABA-A/genética , Aprendizagem Espacial/efeitos dos fármacos
5.
Elife ; 52016 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-27136678

RESUMO

Adolescent synaptic pruning is thought to enable optimal cognition because it is disrupted in certain neuropathologies, yet the initiator of this process is unknown. One factor not yet considered is the α4ßδ GABAA receptor (GABAR), an extrasynaptic inhibitory receptor which first emerges on dendritic spines at puberty in female mice. Here we show that α4ßδ GABARs trigger adolescent pruning. Spine density of CA1 hippocampal pyramidal cells decreased by half post-pubertally in female wild-type but not α4 KO mice. This effect was associated with decreased expression of kalirin-7 (Kal7), a spine protein which controls actin cytoskeleton remodeling. Kal7 decreased at puberty as a result of reduced NMDAR activation due to α4ßδ-mediated inhibition. In the absence of this inhibition, Kal7 expression was unchanged at puberty. In the unpruned condition, spatial re-learning was impaired. These data suggest that pubertal pruning requires α4ßδ GABARs. In their absence, pruning is prevented and cognition is not optimal.


Assuntos
Espinhas Dendríticas/fisiologia , Hipocampo/fisiopatologia , Plasticidade Neuronal , Células Piramidais/fisiologia , Receptores de GABA-A/metabolismo , Animais , Feminino , Camundongos , Puberdade
6.
Psychiatry Res ; 200(2-3): 635-40, 2012 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-22770765

RESUMO

Neurocognitive deficits and their relationship with symptoms have been documented in schizophrenia and at-risk samples. Limited research has examined relationships of schizotypal traits with cognitive functioning among nonclinical samples. To expand this literature and elucidate a dimensional model of psychosis-proneness, we examined the relationship of schizotypal traits with estimated intellectual functioning, simple and complex attention/working memory, verbal fluency and visuospatial abilities in a nonclinical sample of 63 young adults. As hypothesized, aspects of neurocognition were more closely associated with negative (than positive or disorganized) schizotypal traits. For the total sample, poorer visuospatial performance was associated with more negative and overall schizotypal traits. The magnitude of the majority of findings was strengthened after controlling for depression and anxiety. No other findings were significant. Results partially support Meehl's (1962, 1990) view that processes underlying schizophrenia are expressed along a continuum. Findings suggest a relationship of schizotypal traits with neurocognition that is differentiated by trait dimensions, beyond the contribution of general psychiatric symptoms. Findings have implications for better understanding etiology and potential risk factors for psychosis. While sex distribution did not enable direct examination of sex effects, evidence in the field argues for continued exploration of differential patterns by sex.


Assuntos
Transtornos Cognitivos/diagnóstico , Cognição , Transtorno da Personalidade Esquizotípica/diagnóstico , Adolescente , Adulto , Ansiedade/diagnóstico , Ansiedade/psicologia , Transtornos Cognitivos/psicologia , Depressão/diagnóstico , Depressão/psicologia , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Psicologia do Esquizofrênico , Transtorno da Personalidade Esquizotípica/psicologia , Inquéritos e Questionários
7.
Psychiatry Res ; 188(3): 453-5, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21620486

RESUMO

This pilot study tested whether posttraumatic stress disorder (PTSD) patients with impaired conditioned fear acquisition were refractory to open-label duloxetine treatment. Patients with a differential conditioned fear response at pre-treatment subsequently demonstrated significant reductions in PTSD symptoms. These data provide initial evidence of a putative biomarker of selective treatment response in PTSD.


Assuntos
Antidepressivos/uso terapêutico , Condicionamento Psicológico , Medo , Transtornos de Estresse Pós-Traumáticos , Tiofenos/uso terapêutico , Cloridrato de Duloxetina , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Projetos Piloto , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Veteranos
8.
J Neurotrauma ; 27(8): 1541-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20504156

RESUMO

A hallmark of severe traumatic brain injury (TBI) is the development of post-traumatic epilepsy (PTE). However, the mechanisms underlying PTE remain poorly understood. In this study, we used a controlled cortical impact (CCI) model in rats to examine post-traumatic changes in neocortical excitability. Neocortical slices were prepared from rats at 7-9 days (week 1) and 14-16 days (week 2) after CCI injury. By week 2, we observed a substantial gray matter lesion with a cavity that extended to the hippocampal structure. Fluoro-Jade B staining of slices revealed active neuronal degeneration during weeks 1 and 2. Intracellular and extracellular recordings obtained from layer V revealed evoked and spontaneous epileptiform discharges in neocortices of CCI-injured rats. At week 1, intracellular recordings from pyramidal cells revealed evoked epileptiform firing that was synchronized with population events recorded extracellularly, suggestive of increased excitability. This activity was characterized by bursts of action potentials that were followed by recurrent, repetitive after-discharges. At week 2, both spontaneous and evoked epileptiform firing were recorded in slices from injured rats. The evoked discharges resembled those observed at week 1, but with longer burst durations. Spontaneous activity included prolonged, ictal-like discharges lasting up to 8-10 sec, and briefer interictal-like burst events (<1 sec). These results indicate that during the first 2 weeks following severe CCI injury, there is a progressive development of neocortical hyperexcitability that ultimately leads to spontaneous epileptiform firing, suggesting a rapid epileptogenic process.


Assuntos
Lesões Encefálicas/complicações , Epilepsia/etiologia , Epilepsia/fisiopatologia , Neocórtex/fisiopatologia , Animais , Lesões Encefálicas/patologia , Eletroencefalografia , Eletrofisiologia , Epilepsia/patologia , Técnicas In Vitro , Potenciais da Membrana/fisiologia , Neocórtex/patologia , Rede Nervosa/patologia , Rede Nervosa/fisiopatologia , Técnicas de Patch-Clamp , Células Piramidais/patologia , Ratos , Ratos Sprague-Dawley
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