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1.
Clin Neurophysiol ; 132(8): 1770-1776, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34130243

RESUMO

OBJECTIVES: Major Depressive Disorder (MDD) is associated with glutamatergic alterations, including the N-methyl-D-aspartate receptor (NMDA-R). The NMDA-R plays an important role in synaptic plasticity, and individuals with MDD have been shown to have impairments in repetitive Transcranial Magnetic Stimulation (rTMS) motor plasticity. Here, we test whether D-cycloserine, a NMDA-R partial agonist, can rescue TMS motor plasticity in MDD. METHODS: We conducted randomized double-blind placebo-controlled crossover studies in healthy (n = 12) and MDD (n = 12) participants. We stimulated motor cortex using TMS intermittent theta burst stimulation (iTBS) with placebo or D-cycloserine (100 mg). Motor evoked potentials (MEPs) were sampled before and after iTBS. Stimulus response curves (SRC) were characterized at baseline, +90 minutes, and the following day. RESULTS: Acute iTBS MEP facilitation is reduced in MDD and is not rescued by D-cycloserine. After iTBS, SRCs shift to indicate sustained decrease in excitability in healthy participants, yet increased in excitability in MDD participants. D-cycloserine normalized SRC changes from baseline to the following day in MDD participants. In both healthy and MDD participants, D-cycloserine stabilized changes in SRC. CONCLUSION: MDD is associated with alterations in motor plasticity that are rescued and stabilized by NMDA-R agonism. SIGNIFICANCE: Agonism of NMDA receptors rescues iTBS motor plasticity in MDD.


Assuntos
Ciclosserina/uso terapêutico , Transtorno Depressivo Maior/terapia , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Ritmo Teta/fisiologia , Estimulação Magnética Transcraniana/métodos , Adulto , Estudos Cross-Over , Ciclosserina/farmacologia , Transtorno Depressivo Maior/fisiopatologia , Método Duplo-Cego , Potencial Evocado Motor/efeitos dos fármacos , Potencial Evocado Motor/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/fisiologia , Ritmo Teta/efeitos dos fármacos , Adulto Jovem
2.
Psychopharmacology (Berl) ; 238(8): 2325-2334, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33944972

RESUMO

RATIONALE: Schizophrenia patients consistently show deficits in sensory-evoked broadband gamma oscillations and click-evoked entrainment at 40 Hz, called the 40-Hz auditory steady-state response (ASSR). Since such evoked oscillations depend on cortical N-methyl D-aspartic acid (NMDA)-mediated network activity, they can serve as pharmacodynamic biomarkers in the preclinical and clinical development of drug candidates engaging these circuits. However, there are few test-retest reliability data in preclinical species, a prerequisite for within-subject testing paradigms. OBJECTIVE: We investigated the long-term psychometric stability of these measures in a rodent model. METHODS: Female rats with chronic epidural implants were used to record tone- and 40 Hz click-evoked responses at multiple time points and across six sessions, spread over 3 weeks. We assessed reliability using intraclass correlation coefficients (ICC). Separately, we used mixed-effects ANOVA to examine time and session effects. Individual subject variability was determined using the coefficient of variation (CV). Lastly, to illustrate the importance of long-term measure stability for within-subject testing design, we used low to moderate doses of an NMDA antagonist MK801 (0.025-0.15 mg/kg) to disrupt the evoked response. RESULTS: We found that 40-Hz ASSR showed good reliability (ICC=0.60-0.75), while the reliability of tone-evoked gamma ranged from poor to good (0.33-0.67). We noted time but no session effects. Subjects showed a lower variance for ASSR over tone-evoked gamma. Both measures were dose-dependently attenuated by NMDA antagonism. CONCLUSION: Overall, while both evoked gamma measures use NMDA transmission, 40-Hz ASSR showed superior psychometric properties of higher ICC and lower CV, relative to tone-evoked gamma.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Ritmo Gama/efeitos dos fármacos , Ritmo Gama/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Estimulação Acústica/métodos , Estimulação Acústica/normas , Animais , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Potenciais Evocados Auditivos/efeitos dos fármacos , Potenciais Evocados Auditivos/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Reprodutibilidade dos Testes
3.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946908

RESUMO

Alterations of zinc homeostasis have long been implicated in Parkinson's disease (PD). Zinc plays a complex role as both deficiency and excess of intracellular zinc levels have been incriminated in the pathophysiology of the disease. Besides its role in multiple cellular functions, Zn2+ also acts as a synaptic transmitter in the brain. In the forebrain, subset of glutamatergic neurons, namely cortical neurons projecting to the striatum, use Zn2+ as a messenger alongside glutamate. Overactivation of the cortico-striatal glutamatergic system is a key feature contributing to the development of PD symptoms and dopaminergic neurotoxicity. Here, we will cover recent evidence implicating synaptic Zn2+ in the pathophysiology of PD and discuss its potential mechanisms of actions. Emphasis will be placed on the functional interaction between Zn2+ and glutamatergic NMDA receptors, the most extensively studied synaptic target of Zn2+.


Assuntos
Doença de Parkinson/fisiopatologia , Sinapses/fisiologia , Zinco/fisiologia , Animais , Gânglios da Base/fisiopatologia , Proteínas de Transporte de Cátions/deficiência , Córtex Cerebral/fisiopatologia , Quelantes/farmacologia , Quelantes/uso terapêutico , Corpo Estriado/fisiopatologia , Feminino , Homeostase , Humanos , Líquido Intracelular/metabolismo , Masculino , Camundongos , Camundongos Knockout , Degeneração Neural/fisiopatologia , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Transmissão Sináptica/fisiologia
4.
Nat Commun ; 12(1): 2849, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990590

RESUMO

Long-term depression (LTD) of synaptic strength can take multiple forms and contribute to circuit remodeling, memory encoding or erasure. The generic term LTD encompasses various induction pathways, including activation of NMDA, mGlu or P2X receptors. However, the associated specific molecular mechanisms and effects on synaptic physiology are still unclear. We here compare how NMDAR- or P2XR-dependent LTD affect synaptic nanoscale organization and function in rodents. While both LTDs are associated with a loss and reorganization of synaptic AMPARs, only NMDAR-dependent LTD induction triggers a profound reorganization of PSD-95. This modification, which requires the autophagy machinery to remove the T19-phosphorylated form of PSD-95 from synapses, leads to an increase in AMPAR surface mobility. We demonstrate that these post-synaptic changes that occur specifically during NMDAR-dependent LTD result in an increased short-term plasticity improving neuronal responsiveness of depressed synapses. Our results establish that P2XR- and NMDAR-mediated LTD are associated to functionally distinct forms of LTD.


Assuntos
Proteína 4 Homóloga a Disks-Large/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Trifosfato de Adenosina/administração & dosagem , Animais , Autofagia/fisiologia , Células Cultivadas , Proteína 4 Homóloga a Disks-Large/deficiência , Feminino , Hipocampo/citologia , Hipocampo/fisiologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Modelos Neurológicos , N-Metilaspartato/administração & dosagem , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/fisiologia , Receptores Purinérgicos P2X/fisiologia
5.
PLoS Comput Biol ; 17(5): e1008985, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34033641

RESUMO

Poor context integration, the process of incorporating both previous and current information in decision making, is a cognitive symptom of schizophrenia. The maintenance of the contextual information has been shown to be sensitive to changes in excitation-inhibition (EI) balance. Many regions of the brain are sensitive to EI imbalances, however, so it is unknown how systemic manipulations affect the specific regions that are important to context integration. We constructed a multi-structure, biophysically-realistic agent that could perform context-integration as is assessed by the dot pattern expectancy task. The agent included a perceptual network, a memory network, and a decision making system and was capable of successfully performing the dot pattern expectancy task. Systemic manipulation of the agent's EI balance produced localized dysfunction of the memory structure, which resulted in schizophrenia-like deficits at context integration. When the agent's pyramidal cells were less excitatory, the agent fixated upon the cue and initiated responding later than the default agent, which were like the deficits one would predict that individuals on the autistic spectrum would make. This modelling suggests that it may be possible to parse between different types of context integration deficits by adding distractors to context integration tasks and by closely examining a participant's reaction times.


Assuntos
Psicologia do Esquizofrênico , Encéfalo/fisiologia , Humanos , Inibição Psicológica , Tempo de Reação , Receptores de N-Metil-D-Aspartato/fisiologia
6.
Sci Rep ; 11(1): 8788, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888809

RESUMO

A hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs) has been implicated in the pathogenesis of schizophrenia by clinical and rodent studies. However, to what extent NMDAR-hypofunction in distinct cell-types across the brain causes different symptoms of this disease is largely unknown. One pharmaco-resistant core symptom of schizophrenia is impaired working memory (WM). NMDARs have been suggested to mediate sustained firing in excitatory neurons of the prefrontal cortex (PFC) that might underlie WM storage. However, if NMDAR-hypofunction in prefrontal excitatory neurons may indeed entail WM impairments is unknown. We here investigated this question in mice, in which NMDARs were genetically-ablated in PFC excitatory cells. This cell type-selective NMDAR-hypofunction caused a specific deficit in a delayed-matching-to-position (DMTP) 5-choice-based operant WM task. In contrast, T-maze rewarded alternation and several psychological functions including attention, spatial short-term habituation, novelty-processing, motivation, sociability, impulsivity, and hedonic valuation remained unimpaired at the level of GluN1-hypofunction caused by our manipulation. Our data suggest that a hypofunction of NMDARs in prefrontal excitatory neurons may indeed cause WM impairments, but are possibly not accounting for most other deficits in schizophrenia.


Assuntos
Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Camundongos , Córtex Pré-Frontal/citologia , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/fisiopatologia
7.
J Neurosci ; 41(14): 3040-3050, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827970

RESUMO

Protein phosphatases, by counteracting protein kinases, regulate the reversible phosphorylation of many substrates involved in synaptic plasticity, a cellular model for learning and memory. A prominent phosphatase regulating synaptic plasticity and neurologic disorders is the serine/threonine protein phosphatase 1 (PP1). PP1 has three isoforms (α, ß, and γ, encoded by three different genes), which are regulated by a vast number of interacting subunits that define their enzymatic substrate specificity. In this review, we discuss evidence showing that PP1 regulates synaptic transmission and plasticity, as well as presenting novel models of PP1 regulation suggested by recent experimental evidence. We also outline the required targeting of PP1 by neurabin and spinophilin to achieve substrate specificity at the synapse to regulate AMPAR and NMDAR function. We then highlight the role of inhibitor-2 in regulating PP1 function in plasticity, including its positive regulation of PP1 function in vivo in memory formation. We also discuss the distinct function of the three PP1 isoforms in synaptic plasticity and brain function, as well as briefly discuss the role of inhibitory phosphorylation of PP1, which has received recent emphasis in the regulation of PP1 activity in neurons.


Assuntos
Plasticidade Neuronal/fisiologia , Proteína Fosfatase 1/fisiologia , Transmissão Sináptica/fisiologia , Animais , Humanos , Proteína Fosfatase 1/química , Estrutura Terciária de Proteína , Receptores de N-Metil-D-Aspartato/fisiologia , Transdução de Sinais/fisiologia
8.
Commun Biol ; 4(1): 59, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420383

RESUMO

The NMDA receptor-mediated Ca2+ signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2aN615S), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits. In contrast, the NMDAR antagonist MK-801-induced c-Fos expression is reduced in the hippocampus. Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity. This is associated with exploratory hyperactivity and aberrantly increased and dysregulated levels of attention that can interfere with associative learning, in particular when relevant cues and reward outcomes are disconnected in space and time. Together, our findings provide (i) experimental evidence that the inherent voltage-dependent Ca2+ signaling of NMDA receptors is essential for maintaining appropriate responses to sensory stimuli and (ii) a mechanistic explanation for the neurological manifestations seen in the NMDAR-related human disorders with GRIN2 variant-meidiated intellectual disability and focal epilepsy.


Assuntos
Sinalização do Cálcio , Disfunção Cognitiva/genética , Epilepsia Reflexa/genética , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Aprendizagem por Associação , Transtorno do Deficit de Atenção com Hiperatividade/genética , Hipocampo/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Memória Espacial
9.
Dev Biol ; 469: 144-159, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131707

RESUMO

Bivalve metamorphosis is a developmental transition from a free-living larva to a benthic juvenile (spat), regulated by a complex interaction of neurotransmitters and neurohormones such as L-DOPA and epinephrine (catecholamine). We recently suggested an N-Methyl-D-aspartate (NMDA) receptor pathway as an additional and previously unknown regulator of bivalve metamorphosis. To explore this theory further, we successfully induced metamorphosis in the Pacific oyster, Crassostrea gigas, by exposing competent larvae to L-DOPA, epinephrine, MK-801 and ifenprodil. Subsequently, we cloned three NMDA receptor subunits CgNR1, CgNR2A and CgNR2B, with sequence analysis suggesting successful assembly of functional NMDA receptor complexes and binding to natural occurring agonists and the channel blocker MK-801. NMDA receptor subunits are expressed in competent larvae, during metamorphosis and in spat, but this expression is neither self-regulated nor regulated by catecholamines. In-situ hybridisation of CgNR1 in competent larvae identified NMDA receptor presence in the apical organ/cerebral ganglia area with a potential sensory function, and in the nervous network of the foot indicating an additional putative muscle regulatory function. Furthermore, phylogenetic analyses identified molluscan-specific gene expansions of key enzymes involved in catecholamine biosynthesis. However, exposure to MK-801 did not alter the expression of selected key enzymes, suggesting that NMDA receptors do not regulate the biosynthesis of catecholamines via gene expression.


Assuntos
Catecolaminas/biossíntese , Crassostrea/crescimento & desenvolvimento , Metamorfose Biológica , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Clonagem Molecular , Crassostrea/enzimologia , Crassostrea/genética , Crassostrea/metabolismo , Filogenia , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Subunidades Proteicas/fisiologia , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Alinhamento de Sequência , Análise de Sequência de Proteína
10.
Neuron ; 109(3): 530-544.e6, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33232655

RESUMO

Homeostatic plasticity is hypothesized to bidirectionally regulate neuronal activity around a stable set point to compensate for learning-related plasticity, but to date only upward firing rate homeostasis (FRH) has been demonstrated in vivo. We combined chronic electrophysiology in freely behaving animals with an eye-reopening paradigm to enhance firing in primary visual cortex (V1) and found that neurons bidirectionally regulate firing rates around an individual set point. Downward FRH did not require N-methyl-D-aspartate receptor (NMDAR) signaling and was associated with homeostatic scaling down of synaptic strengths. Like upward FRH, downward FRH was gated by arousal state but in the opposite direction: it occurred during sleep, not during wake. In contrast, firing rate depression associated with Hebbian plasticity happened independently of sleep and wake. Thus, sleep and wake states temporally segregate upward and downward FRH, which might prevent interference or provide unopposed homeostatic compensation when it is needed most.


Assuntos
Potenciais de Ação/fisiologia , Neurônios/fisiologia , Sono/fisiologia , Sinapses/fisiologia , Córtex Visual/fisiologia , Animais , Homeostase/fisiologia , Plasticidade Neuronal/fisiologia , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/fisiologia
11.
Hypertension ; 77(1): 147-157, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296248

RESUMO

Central infusion of Ang II (angiotensin II) has been associated with increased sympathetic outflow resulting in neurogenic hypertension. In the present study, we appraised whether the chronic increase in central Ang II activates the paraventricular nucleus of the hypothalamus (PVN) resulting in elevated sympathetic tone and altered baro- and chemoreflexes. Further, we evaluated the contribution of HIF-1α (hypoxia-inducible factor-1α), a transcription factor involved in enhancing the expression of N-methyl-D-aspartate receptors and thus glutamatergic-mediated sympathetic tone from the PVN. Ang II infusion (20 ng/minute, intracerebroventricular, 14 days) increased mean arterial pressure (126±9 versus 84±4 mm Hg), cardiac sympathetic tone (96±7 versus 75±6 bpm), and decreased cardiac parasympathetic tone (16±2 versus 36±3 versus bpm) compared with saline-infused controls in conscious rats. The Ang II-infused group also showed an impaired baroreflex control of heart rate (-1.50±0.1 versus -2.50±0.3 bpm/mm Hg), potentiation of the chemoreflex pressor response (53±7 versus 30±7 mm Hg) and increased number of FosB-labeled cells (53±3 versus 19±4) in the PVN. Concomitant with the activation of the PVN, there was an increased expression of HIF-1α and N-Methyl-D-Aspartate-type1 receptors in the PVN. Further, Ang II-infusion showed increased renal sympathetic nerve activity (20.5±2.3% versus 6.4±1.9% of Max) and 3-fold enhanced renal sympathetic nerve activity responses to microinjection of N-methyl-D-aspartate (200 pmol) into the PVN of anesthetized rats. Further, silencing of HIF-1α in NG108 cells abrogated the expression of N-methyl-D-aspartate-N-methyl-D-aspartate-type1 induced by Ang II. Taken together, our studies suggest a novel Ang II-HIF-1α-N-methyl-D-aspartate receptor-mediated activation of preautonomic neurons in the PVN, resulting in increased sympathetic outflow and alterations in baro- and chemoreflexes.


Assuntos
Angiotensina II/farmacologia , Ácido Glutâmico/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Hipertensão/fisiopatologia , Rim/inervação , Masculino , N-Metilaspartato/farmacologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia , Sistema Nervoso Simpático/fisiologia
12.
Brain Res ; 1750: 147154, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33068634

RESUMO

Activation of Ca2+/calmodulin kinase II (CaMKII) and the N-Methyl D-aspartate receptor (NMDAR), particularly its GluN2B subunit, contribute to the central sensitization of nociceptive pathways and persistent pain. Using mutant mice wherein the activity-driven binding of CaMKII to S1303 in GluN2B is abrogated (GluN2BKI), this study investigated the importance of this interaction for acute and persistent inflammatory nociception. GluN2BKI, wild type and heterozygote mice did not differ in responses to acute noxious heat stimuli as measured with tail flick, paw flick, or hot plate assays, nor did they differ in their responses to mechanical stimulation with von Frey filaments. Surprisingly, the three genotypes exhibited similar spontaneous pain behaviors and hypersensitivity to heat or mechanical stimuli induced by intraplantar injection of capsaicin; however, GluN2BKI mice did not immediately attend to the paw. WT and GluN2BKI mice also did not differ in the nociceptive behaviors elicited by intraplantar injection of formalin, even though MK801 greatly reduced these behaviors in both genotypes concordant with NMDAR dependence. CaMKII binding to GluN2B at S1303 therefore does not appear to be critical for the development of inflammatory nociception. Finally, intrathecal KN93 reduced formalin-induced nociceptive behaviors in GluN2BKI mice. KN93 does not inhibit CaKMII, but rather binds Ca2+/calmodulin. It has multiple other targets including Ca2+-, Na+- and K+-channels, as well as various kinases. Therefore, the use of GluN2BKI mice provided genetic specificity in assessing the role of CaMKII in inflammatory pain signaling cascades. These results challenge current thinking on the involvement of the CaMKII-NMDAR interaction in inflammatory pain.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Inflamação/metabolismo , Dor/metabolismo , Animais , Sinalização do Cálcio/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Calmodulina/metabolismo , Capsaicina/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade/fisiologia , Dor/fisiopatologia , Ligação Proteica , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia
13.
Neurobiol Learn Mem ; 177: 107343, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33242589

RESUMO

The nucleus reuniens has been shown to support the acquisition, consolidation, maintenance, destabilization upon retrieval, and extinction of aversive memories. However, the direct participation of this thalamic subregion in memory reconsolidation is yet to be examined. The present study addressed this question in contextually fear-conditioned rats. Post-reactivation infusion of the GABAA receptor agonist muscimol, the glutamate N2A-containing NMDA receptor antagonist TCN-201, or the protein synthesis inhibitor anisomycin into the NR induced significant impairments in memory reconsolidation. Administering muscimol or TCN-201 and anisomycin locally, or associating locally infused muscimol or TCN-201 with systemically administered clonidine, an α2-receptor adrenergic agonist that attenuates the noradrenergic tonus associated with memory reconsolidation, produced no further reduction in freezing times when compared with the muscimol-vehicle, TCN-201-vehicle, vehicle-anisomycin, and vehicle-clonidine groups. This pattern of results indicates that such treatment combinations produced no additive/synergistic effects on reconsolidation. It is plausible that NR inactivation and antagonism of glutamate N2A-containing NMDA receptors weakened/prevented the subsequent action of anisomycin and clonidine because they disrupted the early stages of signal transduction pathways involved in memory reconsolidation. It is noteworthy that these pharmacological interventions, either alone or combined, induced no contextual memory specificity changes, as assessed in a later test in a novel and unpaired context. Besides, omitting memory reactivation precluded the impairing effects of muscimol, TCN-201, anisomycin, and clonidine on reconsolidation. Together, the present findings demonstrate interacting mechanisms through which the NR can regulate contextual fear memory restabilization.


Assuntos
Medo/fisiologia , Consolidação da Memória/fisiologia , Núcleos da Linha Média do Tálamo/fisiologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Anisomicina/farmacologia , Clonidina/farmacologia , Medo/psicologia , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/efeitos dos fármacos , Núcleos da Linha Média do Tálamo/metabolismo , Muscimol/farmacologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/fisiologia , Sulfonamidas/farmacologia
14.
Neural Comput ; 33(1): 67-95, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33253030

RESUMO

Mild traumatic brain injury (mTBI) presents a significant health concern with potential persisting deficits that can last decades. Although a growing body of literature improves our understanding of the brain network response and corresponding underlying cellular alterations after injury, the effects of cellular disruptions on local circuitry after mTBI are poorly understood. Our group recently reported how mTBI in neuronal networks affects the functional wiring of neural circuits and how neuronal inactivation influences the synchrony of coupled microcircuits. Here, we utilized a computational neural network model to investigate the circuit-level effects of N-methyl D-aspartate receptor dysfunction. The initial increase in activity in injured neurons spreads to downstream neurons, but this increase was partially reduced by restructuring the network with spike-timing-dependent plasticity. As a model of network-based learning, we also investigated how injury alters pattern acquisition, recall, and maintenance of a conditioned response to stimulus. Although pattern acquisition and maintenance were impaired in injured networks, the greatest deficits arose in recall of previously trained patterns. These results demonstrate how one specific mechanism of cellular-level damage in mTBI affects the overall function of a neural network and point to the importance of reversing cellular-level changes to recover important properties of learning and memory in a microcircuit.


Assuntos
Concussão Encefálica/fisiopatologia , Transtornos da Memória/fisiopatologia , Rememoração Mental/fisiologia , Redes Neurais de Computação , Receptores de N-Metil-D-Aspartato/fisiologia , Encéfalo/fisiopatologia , Humanos , Rede Nervosa/fisiopatologia , Plasticidade Neuronal/fisiologia , Aprendizado de Máquina não Supervisionado
15.
PLoS Comput Biol ; 16(12): e1008303, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33264287

RESUMO

Our ability to manipulate objects relies on tactile inputs from first-order tactile neurons that innervate the glabrous skin of the hand. The distal axon of these neurons branches in the skin and innervates many mechanoreceptors, yielding spatially-complex receptive fields. Here we show that synaptic integration across the complex signals from the first-order neuronal population could underlie human ability to accurately (< 3°) and rapidly process the orientation of edges moving across the fingertip. We first derive spiking models of human first-order tactile neurons that fit and predict responses to moving edges with high accuracy. We then use the model neurons in simulating the peripheral neuronal population that innervates a fingertip. We train classifiers performing synaptic integration across the neuronal population activity, and show that synaptic integration across first-order neurons can process edge orientations with high acuity and speed. In particular, our models suggest that integration of fast-decaying (AMPA-like) synaptic inputs within short timescales is critical for discriminating fine orientations, whereas integration of slow-decaying (NMDA-like) synaptic inputs supports discrimination of coarser orientations and maintains robustness over longer timescales. Taken together, our results provide new insight into the computations occurring in the earliest stages of the human tactile processing pathway and how they may be critical for supporting hand function.


Assuntos
Neurônios/fisiologia , Sinapses/fisiologia , Tato/fisiologia , Potenciais de Ação/fisiologia , Humanos , Modelos Neurológicos , Receptores de AMPA/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia
16.
PLoS Comput Biol ; 16(11): e1008360, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33170856

RESUMO

Astrocytes have been shown to modulate synaptic transmission and plasticity in specific cortical synapses, but our understanding of the underlying molecular and cellular mechanisms remains limited. Here we present a new biophysicochemical model of a somatosensory cortical layer 4 to layer 2/3 synapse to study the role of astrocytes in spike-timing-dependent long-term depression (t-LTD) in vivo. By applying the synapse model and electrophysiological data recorded from rodent somatosensory cortex, we show that a signal from a postsynaptic neuron, orchestrated by endocannabinoids, astrocytic calcium signaling, and presynaptic N-methyl-D-aspartate receptors coupled with calcineurin signaling, induces t-LTD which is sensitive to the temporal difference between post- and presynaptic firing. We predict for the first time the dynamics of astrocyte-mediated molecular mechanisms underlying t-LTD and link complex biochemical networks at presynaptic, postsynaptic, and astrocytic sites to the time window of t-LTD induction. During t-LTD a single astrocyte acts as a delay factor for fast neuronal activity and integrates fast neuronal sensory processing with slow non-neuronal processing to modulate synaptic properties in the brain. Our results suggest that astrocytes play a critical role in synaptic computation during postnatal development and are of paramount importance in guiding the development of brain circuit functions, learning and memory.


Assuntos
Astrócitos/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Modelos Neurológicos , Córtex Somatossensorial/fisiologia , Potenciais de Ação/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Biologia Computacional , Simulação por Computador , Ácido Glutâmico/fisiologia , Humanos , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Córtex Somatossensorial/citologia , Córtex Somatossensorial/crescimento & desenvolvimento , Transmissão Sináptica/fisiologia
17.
Hippocampus ; 30(12): 1356-1370, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33112474

RESUMO

Hippocampal sharp-wave ripples (SWRs) support the reactivation of memory representations, relaying information to neocortex during "offline" and sleep-dependent memory consolidation. While blockade of NMDA receptors (NMDAR) is known to affect both learning and subsequent consolidation, the specific contributions of NMDAR activation to SWR-associated activity remain unclear. Here, we combine biophysical modeling with in vivo local field potential (LFP) and unit recording to quantify changes in SWR dynamics following inactivation of NMDAR. In a biophysical model of CA3-CA1 SWR activity, we find that NMDAR removal leads to reduced SWR density, but spares SWR properties such as duration, cell recruitment and ripple frequency. These predictions are confirmed by experiments in which NMDAR-mediated transmission in rats was inhibited using three different NMDAR antagonists, while recording dorsal CA1 LFP. In the model, loss of NMDAR-mediated conductances also induced a reduction in the proportion of cell pairs that co-activate significantly above chance across multiple events. Again, this prediction is corroborated by dorsal CA1 single-unit recordings, where the NMDAR blocker ketamine disrupted correlated spiking during SWR. Our results are consistent with a framework in which NMDA receptors both promote activation of SWR events and organize SWR-associated spiking content. This suggests that, while SWR are short-lived events emerging in fast excitatory-inhibitory networks, slower network components including NMDAR-mediated currents contribute to ripple density and promote consistency in the spiking content across ripples, underpinning mechanisms for fine-tuning of memory consolidation processes.


Assuntos
Região CA1 Hipocampal/fisiologia , Modelos Neurológicos , Células Piramidais/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Eletrodos Implantados , Antagonistas de Aminoácidos Excitatórios/farmacologia , Células Piramidais/efeitos dos fármacos , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
18.
Biomolecules ; 10(10)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066432

RESUMO

Homocysteine (HCY) molecule combines distinct pharmacological properties as an agonist of N-methyl-d-aspartate receptors (NMDARs) and a reducing agent. Whereas NMDAR activation by HCY was elucidated, whether the redox modulation contributes to its action is unclear. Here, using patch-clamp recording and imaging of intracellular Ca2+, we study dithiothreitol (DTT) effects on currents and Ca2+ responses activated by HCY through native NMDARs and recombinant diheteromeric GluN1/2A, GluN1/2B, and GluN1/2C receptors. Within a wide range (1-800 µM) of [HCY]s, the concentration-activation relationships for recombinant NMDARs revealed a biphasicness. The high-affinity component obtained between 1 and 100 µM [HCY]s corresponding to the NMDAR activation was not affected by 1 mM DTT. The low-affinity phase observed at [HCY]s above 200 µM probably originated from thiol-dependent redox modulation of NMDARs. The reduction of NMDAR disulfide bonds by either 1 mM DTT or 1 mM HCY decreased GluN1/2A currents activated by HCY. In contrast, HCY-elicited GluN1/2B currents were enhanced due to the remarkable weakening of GluN1/2B desensitization. In fact, cleaving NMDAR disulfide bonds in neurons reversed the HCY-induced Ca2+ accumulation, making it dependent on GluN2B- rather than GluN2A-containing NMDARs. Thus, estimated concentrations for the HCY redox effects exceed those in the plasma during intermediate hyperhomocysteinemia but may occur during severe hyperhomocysteinemia.


Assuntos
Homocisteína/farmacologia , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Células Cultivadas , Embrião de Mamíferos , Feminino , Células HEK293 , Humanos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Oxirredução , Gravidez , Subunidades Proteicas/agonistas , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética
19.
J Neurosci ; 40(49): 9414-9425, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33115926

RESUMO

Odors activate distributed ensembles of neurons within the piriform cortex, forming cortical representations of odor thought to be essential to olfactory learning and behaviors. This odor response is driven by direct input from the olfactory bulb, but is also shaped by a dense network of associative or intracortical inputs to piriform, which may enhance or constrain the cortical odor representation. With optogenetic techniques, it is possible to functionally isolate defined inputs to piriform cortex and assess their potential to activate or inhibit piriform pyramidal neurons. The anterior olfactory nucleus (AON) receives direct input from the olfactory bulb and sends an associative projection to piriform cortex that has potential roles in the state-dependent processing of olfactory behaviors. Here, we provide a detailed functional assessment of the AON afferents to piriform in male and female C57Bl/6J mice. We confirm that the AON forms glutamatergic excitatory synapses onto piriform pyramidal neurons; and while these inputs are not as strong as piriform recurrent collaterals, they are less constrained by disynaptic inhibition. Moreover, AON-to-piriform synapses contain a substantial NMDAR-mediated current that prolongs the synaptic response at depolarized potentials. These properties of limited inhibition and slow NMDAR-mediated currents result in strong temporal summation of AON inputs within piriform pyramidal neurons, and suggest that the AON could powerfully enhance activation of piriform neurons in response to odor.SIGNIFICANCE STATEMENT Odor information is transmitted from olfactory receptors to olfactory bulb, and then to piriform cortex, where ensembles of activated neurons form neural representations of the odor. While these ensembles are driven by primary bulbar afferents, and shaped by intracortical recurrent connections, the potential for another early olfactory area, the anterior olfactory nucleus (AON), to contribute to piriform activity is not known. Here, we use optogenetic circuit-mapping methods to demonstrate that AON inputs can significantly activate piriform neurons, as they are coupled to NMDAR currents and to relatively modest disynaptic inhibition. The AON may enhance the piriform odor response, encouraging further study to determine the states or behaviors through which AON potentiates the cortical response to odor.


Assuntos
Córtex Olfatório/fisiologia , Córtex Piriforme/fisiologia , Olfato/fisiologia , Sinapses/fisiologia , Animais , Feminino , Ácido Glutâmico/fisiologia , Masculino , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Aferentes/fisiologia , Odorantes , Bulbo Olfatório/fisiologia , Optogenética , Células Piramidais , Receptores de N-Metil-D-Aspartato/fisiologia
20.
FASEB J ; 34(9): 12239-12254, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33000527

RESUMO

α-Synuclein (α-syn)-induced neurotoxicity has been generally accepted as a key step in the pathogenesis of Parkinson's disease (PD). Microtubule-associated protein tau, which is considered second only to α-syn, has been repeatedly linked with PD in association studies. However, the underlying interaction between these two PD-related proteins in vivo remains unclear. To investigate how the expression of tau affects α-syn-induced neurodegeneration in vivo, we generated triple transgenic mice that overexpressed α-syn A53T mutation in the midbrain dopaminergic neurons (mDANs) with different expression levels of tau. Here, we found that tau had no significant effect on the A53T α-syn-mediated mDANs degeneration. However, tau knockout could modestly promote the formation of α-syn aggregates, accelerate the severe and progressive degeneration of parvalbumin-positive (PV+) neurons in substantia nigra pars reticulata (SNR), accompanied with anxiety-like behavior in aged PD-related α-syn A53T mice. The mechanisms may be associated with A53T α-syn-mediated specifically successive impairment of N-methyl-d-aspartate receptor subunit 2B (NR2B), postsynaptic density-95 (PSD-95) and microtubule-associated protein 1A (MAP1A) in PV+ neurons. Our study indicates that MAP1A may play a beneficial role in preserving the survival of PV+ neurons, and that inhibition of the impairment of NR2B/PSD-95/MAP1A pathway, may be a novel and preferential option to ameliorate α-syn-induced neurodegeneration.


Assuntos
Mutação , Degeneração Neural , Doença de Parkinson/etiologia , Parvalbuminas/análise , Substância Negra/patologia , alfa-Sinucleína/genética , Proteínas tau/fisiologia , Animais , Proteína 4 Homóloga a Disks-Large/fisiologia , Proteínas de Homeodomínio/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/fisiologia , Doença de Parkinson/patologia , Fragmentos de Peptídeos/fisiologia , Agregados Proteicos , Receptores de N-Metil-D-Aspartato/fisiologia , Fatores de Transcrição/fisiologia , alfa-Sinucleína/fisiologia , Proteínas tau/química , Proteínas tau/genética
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