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1.
Nat Commun ; 10(1): 3969, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481671

RESUMO

Analyses of idealized feedforward networks suggest that several conditions have to be satisfied in order for activity to propagate faithfully across layers. Verifying these concepts experimentally has been difficult owing to the vast number of variables that must be controlled. Here, we cultured cortical neurons in a chamber with sequentially connected compartments, optogenetically stimulated individual neurons in the first layer with high spatiotemporal resolution, and then monitored the subthreshold and suprathreshold potentials in subsequent layers. Brief stimuli delivered to the first layer evoked a short-latency transient response followed by sustained activity. Rate signals, carried by the sustained component, propagated reliably through 4 layers, unlike idealized feedforward networks, which tended strongly towards synchrony. Moreover, temporal jitter in the stimulus was transformed into a rate code and transmitted to the last layer. This novel mode of propagation occurred in the balanced excitatory-inhibitory regime and is mediated by NMDA-mediated receptors and recurrent activity.


Assuntos
Neurônios/fisiologia , Transdução de Sinais , Potenciais de Ação , Animais , Células Cultivadas , Córtex Cerebral/citologia , Feminino , Masculino , Camundongos , Neurônios/citologia , Optogenética , Tempo de Reação/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia
2.
Psychopharmacology (Berl) ; 236(12): 3451-3463, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31267156

RESUMO

RATIONALE: The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is known to have not only a rapid antidepressant effect but also dissociative side effects. Traxoprodil and lanicemine, also NMDA antagonists, are candidate antidepressant drugs with fewer side effects. OBJECTIVES: In order to understand their mechanism of action, we investigated the acute effects of traxoprodil and lanicemine on brain connectivity using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Functional connectivity (FC) alterations were examined using interregional correlation networks. Graph theoretical methods were used for whole brain network analysis. As interest in NMDAR antagonists as potential antidepressants was triggered by the antidepressant effect of ketamine, results were compared to previous findings from our ketamine studies. RESULTS: Similar to ketamine but to a smaller extent, traxoprodil increased hippocampal-prefrontal (Hc-PFC) coupling. Unlike ketamine, traxoprodil decreased connectivity within the PFC. Lanicemine had no effect on these properties. The improvement of Hc-PFC coupling corresponds well to clinical result, showing ketamine to have a greater antidepressant effect than traxoprodil, while lanicemine has a weak and transient effect. Connectivity changes overlapping between the drugs as well as alterations of local network properties occurred mostly in reward-related regions. CONCLUSION: The antidepressant effect of NMDA antagonists appears to be associated with enhanced Hc-PFC coupling. The effects on local network properties and regional connectivity suggest that improvement of reward processing might also be important for understanding the mechanisms underlying the antidepressant effects of these drugs.


Assuntos
Hipocampo/efeitos dos fármacos , Fenetilaminas/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Piridinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Recompensa , Animais , Antidepressivos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/diagnóstico por imagem , Hipocampo/fisiologia , Imagem por Ressonância Magnética/métodos , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia
3.
Behav Neurosci ; 133(4): 428-436, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31294591

RESUMO

Previous work from our laboratory has indicated that temporary inactivation of the basolateral amygdala (BLA) with bupivacaine blocks acquisition, consolidation, and retrieval of an amphetamine conditioned place preference (CPP). The present study was designed to extend this line of investigation by examining whether N-methyl-D-aspartate (NMDA) receptors in the BLA mediate acquisition and extinction of an amphetamine CPP. Adult male Long-Evans rats received bilateral intra-BLA injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 1.25 µg, 2.5 µg, or 5.0 µg) or saline prior to each session of CPP acquisition (Experiment 1). In addition, separate groups of rats received intra-BLA injections of the sodium channel blocker bupivacaine (Experiment 2), AP5 (1.25 µg, 2.5 µg, or 5.0 µg; Experiment 3), or saline prior to each session of CPP extinction training. Results indicated that intra-BLA injection of bupivacaine or AP5 (2.5 or 5.0 µg) disrupted acquisition of an amphetamine CPP. In addition, neural inactivation of the BLA with bupivacaine blocked extinction of CPP. Finally, intra-BLA AP5 injections (2.5 or 5.0 µg) were sufficient to block CPP extinction. The present findings indicate that NMDA receptor activity in the BLA is critical for acquisition and extinction of an amphetamine CPP and may be relevant to understanding the neural mechanisms underlying some aspects of drug seeking and addiction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Anfetamina/metabolismo , Anfetamina/farmacologia , Tonsila do Cerebelo/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/fisiologia , Bupivacaína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Extinção Psicológica/fisiologia , Masculino , Memória/fisiologia , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
4.
Neurosci Lett ; 708: 134350, 2019 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-31247226

RESUMO

Valproic acid has a long-standing reputation of effectively treating the symptoms of not only epilepsy but also psychiatric conditions. In the latter, the exact mechanism by which valproate exerts its effect remains unclear. In this study, epileptiform bursts were recorded from pyramidal neurons in the prefrontal cortex (the brain region thought to be involved in psychiatric disorders) using the patch-clamp technique. An extracellular solution with no magnesium ions and elevated potassium levels that is known to induce epileptiform activity in vitro was used. Because of their short durations, the epileptiform bursts were regarded as interictal-like epileptiform activity, which is believed to be involved in cognitive impairment. Interictal discharges occur in many neuropsychiatric disorders as well as in healthy population. Epileptic activity in prefrontal cortex pyramidal neurons was potently inhibited by two therapeutic concentrations of valproic acid (20 µM and 200 µM). Moreover, valproate suppressed spontaneous excitatory postsynaptic potentials. Epileptiform bursts were fully inhibited by NMDA receptor antagonist, which suggests that epileptiform activity is driven by NMDA receptors. The inhibition of excitability in prefrontal cortex pyramidal neurons by valproate was also shown. This study shows that it is possible to evoke NMDA-dependent epileptiform activity in prefrontal cortex pyramidal neurons in vitro. We suggest that the prefrontal cortex is a good region for studying the influence of drugs on interictal epileptiform activity.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/fisiopatologia , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Ácido Valproico/farmacologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Células Piramidais/fisiologia , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia
5.
Science ; 364(6440): 578-583, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31073064

RESUMO

Young adult-born granule cells (abGCs) in the dentate gyrus (DG) have a profound impact on cognition and mood. However, it remains unclear how abGCs distinctively contribute to local DG information processing. We found that the actions of abGCs in the DG depend on the origin of incoming afferents. In response to lateral entorhinal cortex (LEC) inputs, abGCs exert monosynaptic inhibition of mature granule cells (mGCs) through group II metabotropic glutamate receptors. By contrast, in response to medial entorhinal cortex (MEC) inputs, abGCs directly excite mGCs through N-methyl-d-aspartate receptors. Thus, a critical function of abGCs may be to regulate the relative synaptic strengths of LEC-driven contextual information versus MEC-driven spatial information to shape distinct neural representations in the DG.


Assuntos
Giro Denteado/fisiologia , Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Animais , Células Cultivadas , Potenciais Evocados , Humanos , Camundongos , Camundongos Transgênicos , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/fisiologia
6.
Exp Brain Res ; 237(7): 1593-1614, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079238

RESUMO

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants. The existing studies on neuromodulator-based drugs have focused on recording in the brainstem nuclei, with much less known about their effects on prefrontal or sensory cortex. Studies on neuromodulatory drugs have moreover focused on single unit firing patterns with less emphasis on LFPs, whereas the rapidly acting antidepressant literature shows the opposite trend. In a synthesis of this information, we hypothesize that all classes of antidepressants could have common final effects on limbic circuitry. Whereas NMDA receptor blockade may induce a high powered gamma oscillatory state via direct and fast alteration of glutamatergic systems in mood-related circuits, neuromodulatory antidepressants may induce similar effects over slower timescales, corresponding with the timecourse of response in patients, while resetting synaptic excitatory versus inhibitory signaling to a normal level. Thus, gamma signaling may provide a biomarker (or "neural readout") of the therapeutic effects of all classes of antidepressants.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ritmo Gama/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Antidepressivos/farmacologia , Depressão/fisiopatologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Fenômenos Eletrofisiológicos/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ritmo Gama/fisiologia , Humanos , Córtex Pré-Frontal/fisiopatologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia
7.
J Bioinform Comput Biol ; 17(1): 1940003, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30866729

RESUMO

A computation approach to identify the effect of missense mutations on the protein function is proposed. Using molecular dynamics simulation we have analyzed the gating kinetics of mutant NMDA synaptic receptors carrying mutations in their NR2 subunits. Analysis of channel geometry and Mg ion binding allowed to estimate the receptor conductivity. As a result, it was possible to identify the effect of these mutations on the generation of theta and gamma rhythms by the hippocampal neural network. Obtained results can be adapted for the analysis and evaluation of possible cognitive impairments caused by neurological diseases or consequences of radiation and other negative factors.


Assuntos
Hipocampo/fisiologia , Modelos Neurológicos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/fisiologia , Substituição de Aminoácidos , Animais , Região CA3 Hipocampal/citologia , Região CA3 Hipocampal/fisiologia , Biologia Computacional , Simulação por Computador , Hipocampo/citologia , Humanos , Potenciais da Membrana , Simulação de Dinâmica Molecular , Proteínas Mutantes/genética , Proteínas Mutantes/fisiologia , Mutação de Sentido Incorreto , Subunidades Proteicas , Receptores de N-Metil-D-Aspartato/química
8.
Brain Struct Funct ; 224(4): 1627-1645, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30919051

RESUMO

Rodents extract information about nearby objects from the movement of their whiskers through dynamic computations that are carried out by a network of forebrain structures that includes the thalamus and the primary sensory (S1BF) and motor (M1wk) whisker cortices. The posterior nucleus (Po), a higher order thalamic nucleus, is a key hub of this network, receiving cortical and brainstem sensory inputs and innervating both motor and sensory whisker-related cortical areas. In a recent study in rats, we showed that Po inputs differently impact sensory processing in S1BF and M1wk. Here, in C57BL/6 mice, we measured Po synaptic bouton layer distribution and size, compared cortical unit response latencies to "in vivo" Po activation, and pharmacologically examined the glutamatergic receptor mechanisms involved. We found that, in S1BF, a large majority (56%) of Po axon varicosities are located in layer (L)5a and only 12% in L2-L4, whereas in M1wk this proportion is inverted to 18% and 55%, respectively. Light and electron microscopic measurements showed that Po synaptic boutons in M1wk layers 3-4 are significantly larger (~ 50%) than those in S1BF L5a. Electrical Po stimulation elicits different area-specific response patterns. In S1BF, responses show weak or no facilitation, and involve both ionotropic and metabotropic glutamate receptors, whereas in M1wk, unit responses exhibit facilitation to repetitive stimulation and involve ionotropic NMDA glutamate receptors. Because of the different laminar distribution of axon terminals, synaptic bouton size and receptor mechanisms, the impact of Po signals on M1wk and S1BF, although simultaneous, is likely to be markedly different.


Assuntos
Axônios/fisiologia , Axônios/ultraestrutura , Córtex Motor/fisiologia , Núcleos Posteriores do Tálamo/fisiologia , Córtex Somatossensorial/fisiologia , Sinapses/fisiologia , Sinapses/ultraestrutura , Animais , Estimulação Elétrica , Masculino , Camundongos Endogâmicos C57BL , Córtex Motor/ultraestrutura , Vias Neurais/fisiologia , Vias Neurais/ultraestrutura , Núcleos Posteriores do Tálamo/ultraestrutura , Receptores de Glutamato Metabotrópico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Córtex Somatossensorial/ultraestrutura , Vibrissas/fisiologia
9.
PLoS One ; 14(3): e0213616, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30856226

RESUMO

There is convincing evidence that the deprivation of one sense can lead to adaptive neuronal changes in spared primary sensory cortices. However, the repercussions of late-onset sensory deprivations on functionality of the remaining sensory cortices are poorly understood. Using repeated intrinsic signal imaging we investigated the effects of whisker or auditory deprivation (WD or AD, respectively) on responsiveness of the binocular primary visual cortex (V1) in fully adult mice. The binocular zone of mice is innervated by both eyes, with the contralateral eye always dominating V1 input over ipsilateral eye input, the normal ocular dominance (OD) ratio. Strikingly, we found that 3 days of WD or AD induced a transient shift of OD, which was mediated by a potentiation of V1 input through the ipsilateral eye. This cross-modal effect was accompanied by strengthening of layer 4 synapses in V1, required visual experience through the ipsilateral eye and was mediated by an increase of the excitation/inhibition ratio in V1. Finally, we demonstrate that both WD and AD induced a long-lasting improvement of visual performance. Our data provide evidence that the deprivation of a non-visual sensory modality cross-modally induces experience dependent V1 plasticity and improves visual behavior, even in adult mice.


Assuntos
Dominância Ocular , Plasticidade Neuronal , Privação Sensorial , Córtex Somatossensorial/fisiologia , Córtex Visual/fisiologia , Animais , Fenômenos Eletrofisiológicos , Feminino , Análise de Fourier , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Imagem Óptica , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/fisiologia , Visão Ocular
10.
Neuroscience ; 406: 389-404, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30926548

RESUMO

The over-activation of N-methyl-D-aspartate receptors (NMDARs) is the main cause of neuronal death in brain ischemia. Both the NMDAR and the Acid-sensing ion channel 1a (ASIC1a) are present in the postsynaptic membrane of the central nervous system (CNS) and participate in physiological and pathological processes. However, the specific role played by ASIC1a in these processes remains elusive. We hypothesize that NMDARs are the primary mediators of normal synaptic transmission and excitatory neuronal death, while ASIC1a plays a modulatory role in facilitating NMDAR function. Using various experimental approaches including patch-clamp recordings on hippocampal slices and CHO cells, primary cultures of hippocampal neurons, calcium imaging, Western blot, cDNA transfection studies, and transient middle cerebral artery occlusion (tMCAO) mouse models, we demonstrate that stimulation of ASIC1a facilitates NMDAR function and inhibition of ASIC1a suppresses NMDAR over-activation. One of our key findings is that activation of ASIC1a selectively facilitates the NR1/NR2A/NR2B triheteromeric subtype of NMDAR currents. In accordance, inhibition of ASIC1a profoundly reduced the NMDAR-mediated EPSCs in older mouse brains, which are known to express much higher levels of triheteromeric NMDARs than younger brains. Furthermore, brain infarct sizes were reduced by a greater degree in older mice compared to younger ones when ASIC1a activity was suppressed. These data suggest that ASIC1a activity selectively enhances the function of triheteromeric NMDARs and exacerbates ischemic neuronal death especially in older animal brains. We propose ASIC1a as a novel therapeutic target for preventing and reducing the detrimental effect of brain ischemia in humans.


Assuntos
Bloqueadores do Canal Iônico Sensível a Ácido/administração & dosagem , Canais Iônicos Sensíveis a Ácido/fisiologia , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Proteínas do Tecido Nervoso/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/agonistas , Técnicas de Cultura de Órgãos , Receptores de N-Metil-D-Aspartato/agonistas
11.
Neuropsychopharmacology ; 44(7): 1310-1318, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30723288

RESUMO

N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.


Assuntos
Ansiedade/fisiopatologia , Região CA1 Hipocampal/fisiopatologia , Depressão/fisiopatologia , Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Ansiedade/etiologia , Depressão/etiologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Comportamento Social , Estresse Psicológico/complicações , Sinapses/fisiologia
12.
Neurobiol Learn Mem ; 159: 16-23, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30731234

RESUMO

Working memory (WM), the capacity for short-term storage and manipulation of small quantities of information, depends on fronto-parietal circuits. However, the function of the posterior parietal cortex (PPC) in WM has gone relatively understudied in rodents. Recent evidence calls into question whether the PPC is necessary for all forms of WM. Thus, the present experiment examined the role of the rat PPC in the Trial-Unique Non-matching-to-Location (TUNL) task, a touchscreen-based visuospatial WM task that relies on the rat medial prefrontal cortex (mPFC). Temporary inactivation of the PPC caused by bilateral infusions of muscimol and baclofen significantly impaired accuracy and increased the number of correction trials performed, indicating that the PPC is necessary for performance of TUNL. Additionally, we investigated the effects of blocking NMDA or non-NMDA parietal ionotropic glutamate receptors on TUNL and found that, in contrast to the prefrontal cortex, NMDA receptors in the PPC are not necessary for TUNL performance, whereas blockade of AMPA/Kainate receptors significantly impaired accuracy. These results indicate that performance of the TUNL task depends on the PPC but that NMDA receptor signaling within this brain area is not necessary for intact performance.


Assuntos
Comportamento Animal/fisiologia , Memória de Curto Prazo/fisiologia , Lobo Parietal/metabolismo , Desempenho Psicomotor/fisiologia , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Percepção Espacial/fisiologia , Percepção Visual/fisiologia , Animais , Baclofeno/farmacologia , Comportamento Animal/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Muscimol/farmacologia , Lobo Parietal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Long-Evans , Receptores de AMPA/efeitos dos fármacos , Receptores de Ácido Caínico/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos
13.
Cell Mol Life Sci ; 76(10): 1889-1899, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788514

RESUMO

Chronic neuropathic pain is a debilitating condition that remains challenging to treat. Glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been used to treat neuropathic pain, but the exact sites of their actions have been unclear until recently. Although conventionally postsynaptic, NMDARs are also expressed presynaptically, particularly at the central terminals of primary sensory neurons, in the spinal dorsal horn. However, presynaptic NMDARs in the spinal cord are normally quiescent and are not actively involved in physiological nociceptive transmission. In this review, we describe the emerging role of presynaptic NMDARs at the spinal cord level in chronic neuropathic pain and the implications of molecular mechanisms for more effective treatment. Recent studies indicate that presynaptic NMDAR activity at the spinal cord level is increased in several neuropathic pain conditions but not in chronic inflammatory pain. Increased presynaptic NMDAR activity can potentiate glutamate release from primary afferent terminals to spinal dorsal horn neurons, which is crucial for the synaptic plasticity associated with neuropathic pain caused by traumatic nerve injury and chemotherapy-induced peripheral neuropathy. Furthermore, α2δ-1, previously considered a calcium channel subunit, can directly interact with NMDARs through its C-terminus to increase presynaptic NMDAR activity by facilitating synaptic trafficking of α2δ-1-NMDAR complexes in neuropathic pain caused by chemotherapeutic agents and peripheral nerve injury. Targeting α2δ-1-bound NMDARs with gabapentinoids or α2δ-1 C-terminus peptides can attenuate nociceptive drive form primary sensory nerves to dorsal horn neurons in neuropathic pain.


Assuntos
Neuralgia/fisiopatologia , Dor Nociceptiva/fisiopatologia , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores Pré-Sinápticos/fisiologia , Medula Espinal/fisiopatologia , Animais , Camundongos , Neuralgia/metabolismo , Nociceptividade/fisiologia , Dor Nociceptiva/metabolismo , Nociceptores/metabolismo , Nociceptores/fisiologia , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Pré-Sinápticos/metabolismo
14.
Behav Brain Res ; 363: 77-82, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30711444

RESUMO

Midbrain dopamine (DA) neurons play a crucial role in the formation of conditioned associations between environmental cues and appetitive events. Activation of N-methyl-d-aspartate (NMDA) receptors is a key mechanism responsible for the generation of conditioned responses of DA neurons to reward cues. Here, we tested the effects of the cell type-specific inactivation of NMDA receptors in DA neurons in adult mice on stimulus-reward learning. Animals were trained in a Pavlovian learning paradigm in which they had to learn the predictive value of two conditioned stimuli, one of which (CS+) was paired with the delivery of a water reward. Over the course of conditioning, mutant mice learned that the CS+ predicted reward availability, and they approached the reward receptacle more frequently during CS+ trials than CS- trials. However, conditioned responses to the CS+ were weaker in the mutant mice, possibly indicating that they did not attribute incentive salience to the CS+. To further assess whether the attribution of incentive salience was impaired by the mutation, animals were tested in a conditioned reinforcement test. The test revealed that mutant mice made fewer instrumental responses paired with CS+ presentation, confirming that the CS+ had a weaker incentive value. Taken together, these results indicate that reward prediction learning does occur in the absence of NMDA receptors in DA neurons, but the ability of reward-paired cues to invigorate and reinforce behavior is attenuated.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Motivação/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Condicionamento Clássico/fisiologia , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Aprendizagem/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos , Recompensa
15.
J Biol Rhythms ; 34(1): 39-50, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30654688

RESUMO

The suprachiasmatic nucleus (SCN) is the main brain clock that regulates circadian rhythms in mammals. The SCN synchronizes to the LD cycle through the retinohypothalamic tract (RHT), which projects to ventral SCN neurons via glutamatergic synapses. Released glutamate activates N-methyl-D-aspartate (NMDA) receptors, which play a critical role in the activation of signaling cascades to enable phase shifts. Previous evidence indicates that presynaptic changes during postnatal development consist of an increase in RHT fibers impinging on SCN neurons between postnatal day (P) 1 to 4 and P15. The aim of this study was to evaluate postsynaptic developmental changes in the NR2 subunits that determine the pharmacological and biophysical properties of the neuronal NMDA receptors in the ventral SCN. To identify the expression of NR2 subtypes, we utilized RT-PCR, immunohistochemical fluorescence, and electrophysiological recordings of synaptic activity. We identified development-dependent changes in NR2A, C, and D subtypes in mRNA and protein expression, whereas NR2B protein was equally present at all analyzed postnatal ages. The NR2A antagonist PEAQX (100 nM) reduced the frequency of NMDA excitatory postsynaptic currents (EPSCs) at P8 significantly more than at P34, but the antagonists for NR2B (3 µM Ro 25-6981) and NR2C/D (150 nM PPDA) did not influence NMDA EPSCs differently at the 2 analyzed postnatal ages. Our results point to P8 as the earliest analyzed postnatal age that shows mRNA and protein expression similar to those found at the juvenile stage P34. Taken together, our findings indicate that postsynaptic development-dependent modifications in the NR2 subtypes of the NMDA receptor could be important for the synchronization of ventral SCN neurons to the LD cycle at adult stages.


Assuntos
Envelhecimento , Ritmo Circadiano , Receptores de N-Metil-D-Aspartato/fisiologia , Neurônios do Núcleo Supraquiasmático/fisiologia , Animais , Encéfalo/fisiologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sinapses/fisiologia
16.
Psychiatr Genet ; 29(2): 44-50, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30664045

RESUMO

BACKGROUND: Several lines of evidence support the hypothesis that impaired functioning of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) might be involved in the etiology of schizophrenia. NMDAR is activated by phosphorylation by Fyn, and there is also some evidence to suggest that abnormalities in Fyn functionality could also be involved in susceptibility to schizophrenia. In a recent weighted burden analysis of exome-sequenced schizophrenia cases and controls, we noted modest statistical evidence for an enrichment of rare, functional variants in FYN, GRIN1, and GRIN2B in schizophrenia cases. AIM: To test the plausibility of the hypothesis that schizophrenia susceptibility might be associated with genetic variants predicted to cause impaired functioning of NMDAR, either directly or indirectly through impairment of the kinases that phosphorylate it. METHODS: In an exome-sequenced sample of 4225 schizophrenia cases and 5834 controls, rare variants occurring in genes for the NMDAR subunits and for the kinases acting on it were annotated. The counts of disruptive and damaging variants were compared between cases and controls, and the distribution of amino acids affected by damaging variants was visualised in ProteinPaint and the RCSB Protein Data Bank. Special attention was paid to tyrosine residues subject to phosphorylation. RESULTS: There was no suggestion that abnormalities of the serine-threonine kinases or of Src were associated with schizophrenia. Overall, three cases and no controls had a disruptive variant in GRIN2A and two cases and no controls had a disruptive variant in FYN. Moreover, 14 cases and three controls had damaging variants in FYN, and all the variants in controls affected amino acid residues in the N-terminal region outside of any known functional domains. By contrast, 10 variants in cases affected amino acids in functional domains, and in the 3D structure of Fyn, two of the amino acid substitutions, A376T and Q517E, were adjacent to each other. A total of eight cases and one control had damaging variants in GRIN1, but there was no obvious pattern with respect to particular functional domains being affected in this or other genes. A single case had a variant in GRIN2A affecting a well-supported phosphorylation site, Y943C, and three cases had a variant in FYN which produces an amino acid change, T216S, which lies two residues away from two adjacent well-supported phosphorylation sites. Aside from this, there was no suggestion that tyrosine phosphorylation sites in Fyn or NMDAR were affected. CONCLUSION: The numbers of variants involved are too small for firm conclusions to be drawn. The results are consistent with the hypothesis that ∼0.5% of patients with schizophrenia have disruptive or damaging genetic variants, which could plausibly impair functioning of NMDAR directly or indirectly through impairing Fyn function.


Assuntos
Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Simulação por Computador , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas c-fyn/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Sequenciamento Completo do Exoma/métodos
17.
Neuroscience ; 402: 23-36, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30685540

RESUMO

FKBP5 (FKBP51) is a glucocorticoid receptor (GR) binding protein, which acts as a co-chaperone of heat shock protein 90 (HSP90) and negatively regulates GR. Its association with mental disorders has been identified, but its function in disease development is largely unknown. Long-term potentiation (LTP) is a functional measurement of neuronal connection and communication, and is considered one of the major cellular mechanisms that underlies learning and memory, and is disrupted in many mental diseases. In this study, a reduction in LTP in Fkbp5 knockout (KO) mice was observed when compared to WT mice, which correlated with changes to the glutamatergic and GABAergic signaling pathways. The frequency of mEPSCs was decreased in KO hippocampus, indicating a decrease in excitatory synaptic activity. While no differences were found in levels of glutamate between KO and WT, a reduction was observed in the expression of excitatory glutamate receptors (NMDAR1, NMDAR2B and AMPAR), which initiate and maintain LTP. The expression of the inhibitory neurotransmitter GABA was found to be enhanced in Fkbp5 KO hippocampus. Further investigation suggested that increased expression of GAD65, but not GAD67, accounted for this increase. Additionally, a functional GABAergic alteration was observed in the form of increased mIPSC frequency in the KO hippocampus, indicating an increase in presynaptic GABA release. Our findings uncover a novel role for Fkbp5 in neuronal synaptic plasticity and highlight the value of Fkbp5 KO as a model for studying its role in neurological function and disease development.


Assuntos
Hipocampo/fisiologia , Potenciação de Longa Duração , Neurônios/fisiologia , Proteínas de Ligação a Tacrolimo/fisiologia , Animais , Comportamento Animal , Ácido Glutâmico/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Potenciais Pós-Sinápticos em Miniatura , Receptores de AMPA/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Proteínas de Ligação a Tacrolimo/genética , Ácido gama-Aminobutírico/fisiologia
18.
Neuroscience ; 400: 33-47, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30605702

RESUMO

Lactating female mice nurture their pups and attack intruders in their territory. When an intruder invades a dam's territory, she needs to switch her behavior from care to aggression to protect her pups and territory. Although the neuronal mechanisms underlying each distinct behavior have been studied, it is unclear how these behaviors are displayed alternatively. The dorsal raphe nucleus (DRN) regulates both nurturing and aggressive behaviors. In the present study, we examined whether the DRN is involved in regulating alternative display of maternal care and aggression. We first examined neuronal activity in the medial prefrontal cortex (mPFC) and lateral habenula (LHb), which send glutamatergic input to the DRN, in dams by injecting Fluorogold, a retrograde tracer, into the DRN. The number of c-Fos- and Fluorogold-positive neurons in the mPFC and LHb increased in the dams that displayed biting behavior in response to an intruder, but remained unchanged in the dams that displayed nurturing behavior. Injections of N-methyl-d-aspartic acid (NMDA) receptor antagonists or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonists into the DRN inhibited biting behavior but not nurturing behavior. In contrast, injections of NMDA or AMPA into the DRN inhibited nurturing behavior. These results suggest that glutamatergic signals in the DRN, which may originate from the mPFC and/or LHb, regulate the preferential display of biting behavior over nurturing behavior in dams.


Assuntos
Agressão/fisiologia , Núcleo Dorsal da Rafe/fisiologia , Ácido Glutâmico/fisiologia , Comportamento Materno/fisiologia , Neurônios/fisiologia , Receptores Ionotrópicos de Glutamato/fisiologia , Animais , Feminino , Habenula/fisiologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia
19.
Neurochem Res ; 44(3): 531-538, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30109556

RESUMO

Since the discovery of NMDA receptor (NMDAR) dependent long-term potentiation (LTP) in the hippocampus, many studies have demonstrated that NMDAR dependent LTP exists throughout central synapses, including those involved in sensory transmission and perception. NMDAR LTP has been reported in spinal cord dorsal horn synapses, anterior cingulate cortex and insular cortex. Behavioral, genetic and pharmacological studies show that inhibiting or reducing NMDAR LTP produced analgesic effects in animal models of chronic pain. Investigation of signalling mechanisms for NMDAR LTP may provide novel targets for future treatment of chronic pain.


Assuntos
Dor Crônica/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Dor Crônica/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Humanos , Potenciação de Longa Duração/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/fisiologia
20.
Keio J Med ; 68(1): 1-16, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29794368

RESUMO

Living organisms enantioselectively employ L-amino acids as the molecular architecture of protein synthesized in the ribosome. Although L-amino acids are dominantly utilized in most biological processes, accumulating evidence points to the distinctive roles of D-amino acids in non-ribosomal physiology. Among the three domains of life, bacteria have the greatest capacity to produce a wide variety of D-amino acids. In contrast, archaea and eukaryotes are thought generally to synthesize only two kinds of D-amino acids: D-serine and D-aspartate. In mammals, D-serine is critical for neurotransmission as an endogenous coagonist of N-methyl D-aspartate receptors. Additionally, D-aspartate is associated with neurogenesis and endocrine systems. Furthermore, recognition of D-amino acids originating in bacteria is linked to systemic and mucosal innate immunity. Among the roles played by D-amino acids in human pathology, the dysfunction of neurotransmission mediated by D-serine is implicated in psychiatric and neurological disorders. Non-enzymatic conversion of L-aspartate or L-serine residues to their D-configurations is involved in age-associated protein degeneration. Moreover, the measurement of plasma or urinary D-/L-serine or D-/L-aspartate levels may have diagnostic or prognostic value in the treatment of kidney diseases. This review aims to summarize current understanding of D-amino-acid-associated biology with a major focus on mammalian physiology and pathology.


Assuntos
Aminoácidos/química , Ácido D-Aspártico/química , Nefropatias/metabolismo , Doenças do Sistema Nervoso/metabolismo , Transtornos Psicóticos/metabolismo , Serina/química , Aminoácidos/biossíntese , Aminoácidos/imunologia , Animais , Archaea/metabolismo , Bactérias/metabolismo , Ácido D-Aspártico/biossíntese , Ácido D-Aspártico/imunologia , Sistema Endócrino/fisiologia , Humanos , Imunidade Inata , Imunidade nas Mucosas , Nefropatias/patologia , Nefropatias/fisiopatologia , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Neurogênese/fisiologia , Biossíntese de Proteínas/fisiologia , Transtornos Psicóticos/patologia , Transtornos Psicóticos/fisiopatologia , Receptores de N-Metil-D-Aspartato/fisiologia , Serina/biossíntese , Serina/imunologia , Estereoisomerismo , Transmissão Sináptica/fisiologia
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