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1.
Proc Natl Acad Sci U S A ; 117(1): 650-655, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31843894

RESUMO

Even a brief exposure to severe stress strengthens synaptic connectivity days later in the amygdala, a brain area implicated in the affective symptoms of stress-related psychiatric disorders. However, little is known about the synaptic signaling mechanisms during stress that eventually culminate in its delayed impact on the amygdala. Hence, we investigated early stress-induced changes in amygdalar synaptic signaling in order to prevent its delayed effects. Whole-cell recordings in basolateral amygdala (BLA) slices from rats revealed higher frequency of miniature excitatory postsynaptic currents (mEPSCs) immediately after 2-h immobilization stress. This was replicated by inhibition of cannabinoid receptors (CB1R), suggesting a role for endocannabinoid (eCB) signaling. Stress also reduced N-arachidonoylethanolamine (AEA), an endogenous ligand of CB1R. Since stress-induced activation of fatty acid amide hydrolase (FAAH) reduces AEA, we confirmed that oral administration of an FAAH inhibitor during stress prevents the increase in synaptic excitation in the BLA soon after stress. Although stress also caused an immediate reduction in synaptic inhibition, this was not prevented by FAAH inhibition. Strikingly, FAAH inhibition during the traumatic stressor was also effective 10 d later on the delayed manifestation of synaptic strengthening in BLA neurons, preventing both enhanced mEPSC frequency and increased dendritic spine-density. Thus, oral administration of an FAAH inhibitor during a brief stress prevents the early synaptic changes that eventually build up to hyperexcitability in the amygdala. This framework is of therapeutic relevance because of growing interest in targeting eCB signaling to prevent the gradual development of emotional symptoms and underlying amygdalar dysfunction triggered by traumatic stress.


Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Emoções/efeitos dos fármacos , Endocanabinoides/metabolismo , Transdução de Sinais/fisiologia , Estresse Psicológico/fisiopatologia , Administração Oral , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Antagonistas de Receptores de Canabinoides/administração & dosagem , Modelos Animais de Doenças , Emoções/fisiologia , Inibidores Enzimáticos/administração & dosagem , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Humanos , Masculino , Ratos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologia
2.
Nat Neurosci ; 22(12): 2000-2012, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712775

RESUMO

Acquisition and extinction of learned fear responses utilize conserved but flexible neural circuits. Here we show that acquisition of conditioned freezing behavior is associated with dynamic remodeling of relative excitatory drive from the basolateral amygdala (BLA) away from corticotropin releasing factor-expressing (CRF+) centrolateral amygdala neurons, and toward non-CRF+ (CRF-) and somatostatin-expressing (SOM+) neurons, while fear extinction training remodels this circuit back toward favoring CRF+ neurons. Importantly, BLA activity is required for this experience-dependent remodeling, while directed inhibition of the BLA-centrolateral amygdala circuit impairs both fear memory acquisition and extinction memory retrieval. Additionally, ectopic excitation of CRF+ neurons impairs fear memory acquisition and facilities extinction, whereas CRF+ neuron inhibition impairs extinction memory retrieval, supporting the notion that CRF+ neurons serve to inhibit learned freezing behavior. These data suggest that afferent-specific dynamic remodeling of relative excitatory drive to functionally distinct subcortical neuronal output populations represents an important mechanism underlying experience-dependent modification of behavioral selection.


Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Núcleo Central da Amígdala/fisiologia , Medo/fisiologia , Ácido Glutâmico/fisiologia , Animais , Condicionamento Clássico/fisiologia , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Extinção Psicológica/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Camundongos Transgênicos , Vias Neurais/fisiologia , Somatostatina/genética , Somatostatina/metabolismo
3.
Nat Neurosci ; 22(12): 1986-1999, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719672

RESUMO

The importance of neuronal ensembles, termed engram cells, in storing and retrieving memory is increasingly being appreciated, but less is known about how these engram cells operate within neural circuits. Here we tagged engram cells in the ventral CA1 region of the hippocampus (vCA1) and the core of the nucleus accumbens (AcbC) during cocaine conditioned place preference (CPP) training and show that the vCA1 engram projects preferentially to the AcbC and that the engram circuit from the vCA1 to the AcbC mediates memory recall. Direct activation of the AcbC engram while suppressing the vCA1 engram is sufficient for cocaine CPP. The AcbC engram primarily consists of D1 medium spiny neurons, but not D2 medium spiny neurons. The preferential synaptic strengthening of the vCA1→AcbC engram circuit evoked by cocaine conditioning mediates the retrieval of cocaine CPP memory. Our data suggest that the vCA1 engram stores specific contextual information, while the AcbC D1 engram and its downstream network store both cocaine reward and associated contextual information, providing a potential mechanism by which cocaine CPP memory is stored.


Assuntos
Região CA1 Hipocampal/fisiologia , Cocaína/farmacologia , Rememoração Mental/fisiologia , Núcleo Accumbens/fisiologia , Animais , Comportamento Animal/fisiologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Camundongos Transgênicos , Vias Neurais/fisiologia , Optogenética , Receptores Dopaminérgicos/fisiologia
4.
Nat Neurosci ; 22(11): 1806-1819, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636448

RESUMO

Prediabetes and Alzheimer's disease both increase in prevalence with age. The former is a risk factor for the latter, but a mechanistic linkage between them remains elusive. We show that prediabetic serum hyperinsulinemia is reflected in the cerebrospinal fluid and that this chronically elevated insulin renders neurons resistant to insulin. This leads to abnormal electrophysiological activity and other defects. In addition, neuronal insulin resistance reduces hexokinase 2, thus impairing glycolysis. This hampers the ubiquitination and degradation of p35, favoring its cleavage to p25, which hyperactivates CDK5 and interferes with the GSK3ß-induced degradation of ß-catenin. CDK5 contributes to neuronal cell death while ß-catenin enters the neuronal nucleus and re-activates the cell cycle machinery. Unable to successfully divide, the neuron instead enters a senescent-like state. These findings offer a direct connection between peripheral hyperinsulinemia, as found in prediabetes, age-related neurodegeneration and cognitive decline. The implications for neurodegenerative conditions such as Alzheimer's disease are described.


Assuntos
Envelhecimento/fisiologia , Ciclo Celular/fisiologia , Senescência Celular/fisiologia , Hiperinsulinismo/fisiopatologia , Resistência à Insulina/fisiologia , Neurônios/fisiologia , Animais , Morte Celular/fisiologia , Senescência Celular/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Hexoquinase/metabolismo , Hiperinsulinismo/líquido cefalorraquidiano , Potenciais Pós-Sinápticos Inibidores/fisiologia , Insulina/farmacologia , Liraglutida/farmacologia , Masculino , Aprendizagem em Labirinto/fisiologia , Metformina/farmacologia , Camundongos , Neurônios/metabolismo , Fosfotransferases/metabolismo , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/metabolismo , Ubiquitinação/fisiologia , beta Catenina/metabolismo
5.
Muscle Nerve ; 60(6): 790-800, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31531871

RESUMO

INTRODUCTION: Reduced expression of the vesicular acetylcholine transporter (VAChT) leads to changes in the distribution and shape of synaptic vesicles (SVs) at neuromuscular junctions (NMJs), suggesting vesicular acetylcholine (ACh) as a key component of synaptic structure and function. It is poorly understood how long-term changes in cholinergic transmission contribute to age- and disease-related degeneration in the motor system. METHODS: In this study we performed confocal imaging, electrophysiology, electron microscopy, and analyses of respiratory mechanics of the diaphragm NMJ components in 12-month-old wild-type (WT) and VAChTKDHOM mice. RESULTS: Diaphragms of NMJs of the VAChTKDHOM mice were similar to those in WT mice in number, colocalization, and fragmentation of pre-/postsynaptic components. However, they had increased spontaneous SV exocytosis, miniature endplate potential frequency, and diminished MEPP amplitude. No impairment in respiratory mechanics at rest was observed, probably due to the large neurotransmission safety factor of the diaphragm. DISCUSSION: The present findings help us to understand the consequences of reduced ACh release at the NMJs during aging.


Assuntos
Envelhecimento/patologia , Diafragma/ultraestrutura , Síndromes Miastênicas Congênitas/patologia , Junção Neuromuscular/ultraestrutura , Vesículas Sinápticas/ultraestrutura , Acetilcolina/metabolismo , Envelhecimento/metabolismo , Animais , Diafragma/metabolismo , Diafragma/fisiopatologia , Modelos Animais de Doenças , Endocitose , Potenciais Pós-Sinápticos Excitadores/fisiologia , Exocitose , Técnicas de Silenciamento de Genes , Camundongos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Placa Motora , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/metabolismo , Síndromes Miastênicas Congênitas/fisiopatologia , Junção Neuromuscular/metabolismo , Junção Neuromuscular/fisiopatologia , Mecânica Respiratória/fisiologia , Transmissão Sináptica , Vesículas Sinápticas/metabolismo , Proteínas Vesiculares de Transporte de Acetilcolina/genética
6.
PLoS Comput Biol ; 15(8): e1007226, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31381555

RESUMO

We have previously shown that the physiological size of postsynaptic currents maximises energy efficiency rather than information transfer across the retinothalamic relay synapse. Here, we investigate information transmission and postsynaptic energy use at the next synapse along the visual pathway: from relay neurons in the thalamus to spiny stellate cells in layer 4 of the primary visual cortex (L4SS). Using both multicompartment Hodgkin-Huxley-type simulations and electrophysiological recordings in rodent brain slices, we find that increasing or decreasing the postsynaptic conductance of the set of thalamocortical inputs to one L4SS cell decreases the energy efficiency of information transmission from a single thalamocortical input. This result is obtained in the presence of random background input to the L4SS cell from excitatory and inhibitory corticocortical connections, which were simulated (both excitatory and inhibitory) or injected experimentally using dynamic-clamp (excitatory only). Thus, energy efficiency is not a unique property of strong relay synapses: even at the relatively weak thalamocortical synapse, each of which contributes minimally to the output firing of the L4SS cell, evolutionarily-selected postsynaptic properties appear to maximise the information transmitted per energy used.


Assuntos
Modelos Neurológicos , Transmissão Sináptica/fisiologia , Tálamo/fisiologia , Córtex Visual/fisiologia , Potenciais de Ação/fisiologia , Animais , Biologia Computacional , Simulação por Computador , Metabolismo Energético/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Técnicas In Vitro , Neurônios/fisiologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Tálamo/citologia , Córtex Visual/citologia , Vias Visuais/citologia , Vias Visuais/fisiologia
7.
Neuron ; 103(4): 617-626.e6, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31257103

RESUMO

The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human embryonic stem cell-derived neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change-of-function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.


Assuntos
Moléculas de Adesão Celular Neuronais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Transtorno Autístico/genética , Moléculas de Adesão Celular Neuronais/genética , Células Cultivadas , Córtex Cerebral/fisiologia , Células-Tronco Embrionárias/citologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Genes Reporter , Ácido Glutâmico/fisiologia , Humanos , Camundongos , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Mutação de Sentido Incorreto , Neurogênese , Neurônios/fisiologia , Fenótipo , Receptores de Glutamato/fisiologia , Especificidade da Espécie , Sinapses/química
8.
Brain Stimul ; 12(6): 1402-1409, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31351911

RESUMO

BACKGROUND: Deep brain stimulation (DBS) is a successful clinical therapy for a wide range of neurological disorders; however, the physiological mechanisms of DBS remain unresolved. While many different hypotheses currently exist, our analyses suggest that high frequency (∼100 Hz) stimulation-induced synaptic suppression represents the most basic concept that can be directly reconciled with experimental recordings of spiking activity in neurons that are being driven by DBS inputs. OBJECTIVE: The goal of this project was to develop a simple model system to characterize the excitatory post-synaptic currents (EPSCs) and action potential signaling generated in a neuron that is strongly connected to pre-synaptic glutamatergic inputs that are being directly activated by DBS. METHODS: We used the Tsodyks-Markram (TM) phenomenological synapse model to represent depressing, facilitating, and pseudo-linear synapses driven by DBS over a wide range of stimulation frequencies. The EPSCs were then used as inputs to a leaky integrate-and-fire neuron model and we measured the DBS-triggered post-synaptic spiking activity. RESULTS: Synaptic suppression was a robust feature of high frequency stimulation, independent of the synapse type. As such, the TM equations were used to define alternative DBS pulsing strategies that maximized synaptic suppression with the minimum number of stimuli. CONCLUSIONS: Synaptic suppression provides a biophysical explanation to the intermittent, but still time-locked, post-synaptic firing characteristics commonly seen in DBS experimental recordings. Therefore, network models attempting to analyze or predict the effects of DBS on neural activity patterns should integrate synaptic suppression into their simulations.


Assuntos
Estimulação Encefálica Profunda/métodos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Modelos Neurológicos , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Animais , Neurônios/fisiologia
9.
Psychopharmacology (Berl) ; 236(11): 3281-3289, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31197434

RESUMO

RATIONALE: Juvenile social isolation (SI) and neglect is associated with a wide range of psychiatric disorders. While dysfunction of the corticolimbic pathway is considered to link various abnormal behaviors in SI models of schizophrenia, the enduring effects of early social deprivation on physiological properties of medium spiny neurons (MSNs) in nucleus accumbens (NAc) are not well understood. OBJECTIVES: This study investigated the impacts of juvenile SI on locomotor activity to methamphetamine (METH) and neurophysiological characteristics of MSNs in the core of NAc. METHODS: Socially isolated C57BL/6 mice experienced single housing for 4 weeks on postnatal day (PND) 21. The locomotor response to METH (1.0 mg/kg) was observed in both socially isolated and group-housed mice at PND 56. The effects of juvenile SI on the excitatory synaptic events in MSNs and the intrinsic excitability of MSNs in NAc core were investigated in other batches during PND 63-70. RESULTS: Socially isolated mice showed locomotor hypersensitivity to METH, although the expression of locomotor sensitization to METH in socially isolated mice was not different from group-housed mice. The recordings from MSNs of SI-reared mice exhibited higher frequency and smaller amplitude of miniature/spontaneous excitatory postsynaptic current than those from group-reared mice. Moreover, SI resulted in increased intrinsic excitability of MSNs in adult mice. CONCLUSIONS: These results demonstrate neuronal hyperactivity in the NAc of socially isolated mice, which could contribute to locomotor hypersensitivity to METH. Furthermore, the findings indicate a biological link between early negative life events and the vulnerability to psychostimulant-induced psychosis in adulthood.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Isolamento Social/psicologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Metanfetamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Gravidez
10.
Neuron ; 103(3): 432-444.e3, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31221559

RESUMO

Subtypes of nucleus accumbens medium spiny neurons (MSNs) promote dichotomous outcomes in motivated behaviors. However, recent reports indicate enhancing activity of either nucleus accumbens (NAc) core MSN subtype augments reward, suggesting coincident MSN activity may underlie this outcome. Here, we report a collateral excitation mechanism in which high-frequency, NAc core dopamine 1 (D1)-MSN activation causes long-lasting potentiation of excitatory transmission (LLP) on dopamine receptor 2 (D2)-MSNs. Our mechanistic investigation demonstrates that this form of plasticity requires release of the excitatory peptide substance P from D1-MSNs and robust cholinergic interneuron activation through neurokinin receptor stimulation. We also reveal that D2-MSN LLP requires muscarinic 1 receptor activation, intracellular calcium signaling, and GluR2-lacking AMPAR insertion. This study uncovers a mechanism for shaping NAc core activity through the transfer of excitatory information from D1-MSNs to D2-MSNs and may provide a means for altering goal-directed behavior through coordinated MSN activity.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Potenciação de Longa Duração/fisiologia , Núcleo Accumbens/fisiologia , Substância P/metabolismo , Potenciais de Ação/fisiologia , Animais , Aprepitanto/farmacologia , Sinalização do Cálcio/fisiologia , Neurônios Colinérgicos/fisiologia , Neurônios Dopaminérgicos/efeitos da radiação , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Motivação , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Núcleo Accumbens/citologia , Estimulação Luminosa , Piperidinas/farmacologia , Receptor Muscarínico M1/fisiologia , Receptores de AMPA/fisiologia , Receptores de Dopamina D1/análise , Receptores de Dopamina D2/análise , Receptores da Neurocinina-1/fisiologia
11.
Brain Struct Funct ; 224(6): 2121-2142, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31165301

RESUMO

Neurofibromatosis type 2 (NF2) patients are prone to develop glial-derived tumors in the peripheral and central nervous system (CNS). The Nf2 gene product -Merlin is not only expressed in glia, but also in neurons of the CNS, where its function still remains elusive. Here, we show that cerebellar Purkinje cells (PCs) of isoform-specific Merlin-deficient mice were innervated by smaller vGluT2-positive clusters at presynaptic terminals than those of wild-type mice. This was paralleled by a reduction in frequency and amplitude of miniature excitatory postsynaptic currents (mEPSC). On the contrary, in conditional transgenic mice in which Merlin expression was specifically ablated in PCs (L7Cre;Nf2fl/fl), we found enlarged vGluT2-positive clusters in their presynaptic buttons together with increased amplitudes of miniature postsynaptic currents. The presynaptic terminals of these PCs innervating neurons of the deep cerebellar nuclei were also enlarged. When exploring mice with Merlin-deficient granule cells (GCs) (Math1Cre;Nf2fl/fl), we found cerebellar extracts to contain higher amounts of vGluT1 present in parallel fiber terminals. In parallel, mEPSC frequency was increased in Math1Cre;Nf2fl/fl mice. On the contrary, VGluT2 clusters in cerebellar glomeruli composed of NF2-deficient presynaptic Mossy fiber terminals and NF2-deficient postsynaptic GC were reduced in size as shown for isoform-specific knockout mice. These changes in Math1Cre;Nf2fl/fl-deficient mice were paralleled by an increased activation of Rac1-Cofilin signaling which is known to impact on cytoskeletal reorganization and synapse formation. Consistent with the observed synaptic alterations in these transgenic mice, we observed altered ultrasonic vocalization, which is known to rely on proper cerebellar function. No gross morphological changes or motor coordination deficits were observed in any of these transgenic mice. We therefore conclude that Merlin does not regulate overall cerebellar development, but impacts on pre- and post-synaptic terminal organization.


Assuntos
Cerebelo/metabolismo , Neurofibromina 2/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Animais , Axônios/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Terminações Pré-Sinápticas/metabolismo , Células de Purkinje/metabolismo
12.
Neuroscience ; 411: 222-236, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31132396

RESUMO

The perirhinal (PER) - lateral entorhinal (LEC) network plays a pivotal role in the information transfer between the neocortex and the hippocampus. Anatomical studies have shown that the connectivity is organized bi-directionally: the superficial layers consist of projections running from the neocortex via the PER-LEC network to the hippocampus while the deep layers form the output pathway back to the neocortex. Although these pathways are characterized anatomically, the functional organization of the superficial and deep connections in the PER-LEC network remains to be revealed. We performed paired recordings of superficial and deep layer principal neurons and found that a larger population of superficial neurons responded with action potential firing in response to superficial cortical input, compared to the deep layer population. This suggested that the superficial network can carry information from the cortex towards the hippocampus. The relation between the excitatory and inhibitory input onto the deep and superficial principal neurons showed that the window of net excitability was larger in superficial principal neurons. We performed paired recordings in superficial layer principal neurons and parvalbumin (PV) expressing interneurons to address how this window of opportunity for spiking is affected in superficial principal neurons. The PV interneuron population initiated inhibition at a very consistent timing with increasing stimulus intensity, whereas the excitation temporally shifted to ensure action potential firing. These data indicate that superficial principal neurons can transmit cortical synaptic input through the PER-LEC network because these neurons have a favorable window of opportunity for spiking in contrast to deep neurons.


Assuntos
Potenciais de Ação/fisiologia , Córtex Entorrinal/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia , Córtex Perirrinal/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Vias Neurais/fisiologia , Sinapses/fisiologia
13.
Neuropharmacology ; 155: 113-120, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132436

RESUMO

The acute toxicity of organophosphorus-based compounds is primarily a result of acetylcholinesterase inhibition in the central and peripheral nervous systems. The resulting cholinergic crisis manifests as seizure, paralysis, respiratory failure and neurotoxicity. Though overstimulation of muscarinic receptors is the mechanistic basis of central organophosphorus (OP) toxicities, short-term changes in synapse physiology that precede OP-induced seizures have not been investigated in detail. To study acute effects of OP exposure on synaptic function, field excitatory postsynaptic potentials (fEPSPs) were recorded from Schaffer collateral synapses in the mouse hippocampus CA1 stratum radiatum during perfusion with various OP compounds. Administration of the OPs paraoxon, soman or VX rapidly and stably depressed fEPSPs via a presynaptic mechanism, while the non-OP proconvulsant tetramethylenedisulfotetramine had no effect on fEPSP amplitudes. OP-induced presynaptic long-term depression manifested prior to interictal spiking, occurred independent of recurrent firing, and did not require NMDA receptor currents, suggesting that it was not mediated by activity-dependent calcium uptake. Pharmacological dissection revealed that the presynaptic endocannabinoid type 1 receptor (CB1R) as well as postsynaptic M1 and M3 muscarinic acetylcholine receptors were necessary for OP-LTD. Administration of CB1R antagonists significantly reduced survival in mice after a soman challenge, revealing an acute protective role for endogenous CB1R signaling during OP exposure. Collectively these data demonstrate that the endocannabinoid system alters glutamatergic synaptic function during the acute response to OP acetylcholinesterase inhibitors.


Assuntos
Inibidores da Colinesterase/toxicidade , Organofosfatos/toxicidade , Receptor CB1 de Canabinoide/metabolismo , Receptores Muscarínicos/metabolismo , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/farmacologia , Técnicas de Cultura de Órgãos , Distribuição Aleatória , Soman/toxicidade
14.
Neuron ; 103(1): 66-79.e12, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31104951

RESUMO

The precision and reliability of synaptic information transfer depend on the molecular organization of voltage-gated calcium channels (VGCCs) within the presynaptic membrane. Alternative splicing of exon 47 affects the C-terminal structure of VGCCs and their affinity to intracellular partners and synaptic vesicles (SVs). We show that hippocampal synapses expressing VGCCs either with exon 47 (CaV2.1+47) or without (CaV2.1Δ47) differ in release probability and short-term plasticity. Tracking single channels revealed transient visits (∼100 ms) of presynaptic VGCCs in nanodomains (∼80 nm) that were controlled by neuronal network activity. Surprisingly, despite harboring prominent binding sites to scaffold proteins, CaV2.1+47 persistently displayed higher mobility within nanodomains. Synaptic accumulation of CaV2.1 was accomplished by optogenetic clustering, but only CaV2.1+47 increased transmitter release and enhanced synaptic short-term depression. We propose that exon 47-related alternative splicing of CaV2.1 channels controls synapse-specific release properties at the level of channel mobility-dependent coupling between VGCCs and SVs.


Assuntos
Canais de Cálcio/genética , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Canais de Cálcio/efeitos da radiação , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Células HEK293 , Humanos , Luz , Neurotransmissores/metabolismo , Optogenética , Gravidez , Isoformas de Proteínas/genética , Ratos , Vesículas Sinápticas/fisiologia
15.
Neuropharmacology ; 155: 121-130, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129151

RESUMO

The ability to either erase or update the memories of a previously learned spatial task is an essential process that is required to modify behaviour in a changing environment. Current evidence suggests that the neural representation of such cognitive flexibility involves the balancing of synaptic potentiation (acquisition of memories) with synaptic depression (modulation and updating previously acquired memories). Here we demonstrate that the p38 MAPK/MAPK-activated protein kinase 2 (MK2) cascade is required to maintain the precise tuning of long-term potentiation and long-term depression at CA1 synapses of the hippocampus which is correlated with efficient reversal learning. Using the MK2 knockout (KO) mouse, we show that mGluR-LTD, but not NMDAR-LTD, is markedly impaired in mice aged between 4 and 5 weeks (juvenile) to 7 months (mature adult). Although the amplitude of LTP was the same as in wildtype mice, priming of LTP by the activation of group I metabotropic receptors was impaired in MK2 KO mice. Consistent with unaltered LTP amplitude and compromised mGluR-LTD, MK2 KO mice had intact spatial learning when performing the Barnes maze task, but showed specific deficits in selecting the most efficient combination of search strategies to perform the task reversal. Findings from this study suggest that the mGluR-p38-MK2 cascade is important for cognitive flexibility by regulating LTD amplitude and the priming of LTP.


Assuntos
Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Plasticidade Neuronal/fisiologia , Proteínas Serina-Treonina Quinases/deficiência , Receptores de Glutamato Metabotrópico/metabolismo , Reversão de Aprendizagem/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Depressão Sináptica de Longo Prazo/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Knockout , Técnicas de Cultura de Órgãos , Proteínas Serina-Treonina Quinases/genética
16.
Glia ; 67(9): 1667-1679, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31050055

RESUMO

During postnatal neurodevelopment, excessive synapses must be eliminated by microglia to complete the establishment of neural circuits in the brain. The lack of synaptic regulation by microglia has been implicated in neurodevelopmental disorders such as autism, schizophrenia, and intellectual disability. Here we suggest that vaccinia-related kinase 2 (VRK2), which is expressed in microglia, may stimulate synaptic elimination by microglia. In VRK2-deficient mice (VRK2KO ), reduced numbers of presynaptic puncta within microglia were observed. Moreover, the numbers of presynaptic puncta and synapses were abnormally increased in VRK2KO mice by the second postnatal week. These differences did not persist into adulthood. Even though an increase in the number of synapses was normalized, adult VRK2KO mice showed behavioral defects in social behaviors, contextual fear memory, and spatial memory.


Assuntos
Encéfalo/enzimologia , Encéfalo/crescimento & desenvolvimento , Microglia/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Sinapses/enzimologia , Animais , Encéfalo/citologia , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores/fisiologia , Medo/fisiologia , Humanos , Masculino , Memória/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/citologia , Potenciais Pós-Sinápticos em Miniatura/fisiologia , Proteínas Serina-Treonina Quinases/genética , Comportamento Social , Técnicas de Cultura de Tecidos
17.
Neuroscience ; 410: 183-190, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082535

RESUMO

Neuropeptide Y is a peptide neuromodulator with protective roles including anxiolytic and antidepressant-like effects in animal models of depression and post-traumatic stress disorder. The lateral habenula (LHb) is a brain region that encodes aversive information and is closely related with mood disorders. Although LHb neurons express NPY receptors, the physiological roles of NPY in this region remain uninvestigated. In this study, we examined the actions of NPY on synaptic transmission in the LHb using whole cell patch clamp recording. We observed that NPY inhibited excitatory neurotransmission in a subset of LHb neurons whereas potentiating in a small population of neurons. Inhibitory transmission remained unchanged by NPY application in a subset of neurons but was reduced in the majority of LHb neurons recorded. The overall outcome of NPY application was a decrease in the spontaneous firing rate of the LHb, leading to hypoactivation of the LHb. Our observations indicate that although NPY has divergent effects on excitatory and inhibitory transmission, NPY receptor activation decreases LHb activity, suggesting that the LHb may partly mediate the protective roles of NPY in the central nervous system.


Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Habenula/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Neuropeptídeo Y/farmacologia , Transmissão Sináptica/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Habenula/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos
18.
Neuroscience ; 406: 467-486, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30930131

RESUMO

Obstructive sleep apnea patients face episodes of chronic intermittent hypoxia (CIH), which has been suggested as a causative factor for increased sympathetic activity (SNA) and hypertension. Female rats exposed to CIH develop hypertension and exhibit changes in respiratory-sympathetic coupling, marked by an increase in the inspiratory modulation of SNA. We tested the hypothesis that enhanced inspiratory-modulation of SNA is dependent on carotid bodies (CBs) and are associated with changes in respiratory network activity. For this, in CIH-female rats we evaluated the effect of CBs ablation on respiratory-sympathetic coupling, recorded from respiratory neurons in the working heart-brainstem preparation and from NTS neurons in brainstem slices. CIH-female rats had an increase in peripheral chemoreflex response and in spontaneous excitatory neurotransmission in NTS. CBs ablation prevents the increase in inspiratory modulation of SNA in CIH-female rats. Pre-inspiratory/inspiratory (Pre-I/I) neurons of CIH-female rats have a reduced firing frequency. Post-inspiratory neurons are active for a longer period during expiration in CIH-female rats. Further, using the computational model of a brainstem respiratory-sympathetic network, we demonstrate that a reduction in Pre-I/I neuron firing frequency simulates the enhanced inspiratory SNA modulation in CIH-female rats. We conclude that changes in respiratory-sympathetic coupling in CIH-female rats is dependent on CBs and it is associated with changes in firing properties of specific respiratory neurons types.


Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipóxia/fisiopatologia , Inalação/fisiologia , Rede Nervosa/fisiopatologia , Neurônios/fisiologia , Animais , Corpo Carotídeo/fisiopatologia , Feminino , Ratos , Ratos Wistar
19.
Neurobiol Learn Mem ; 161: 72-82, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30930287

RESUMO

Beta-adrenergic receptor (b-AR) activation by noradrenaline (NA) enhances memory formation and long-term potentiation (LTP), a form of synaptic plasticity characterized by an activity-dependent increase in synaptic strength. LTP is believed to be a cellular mechanism for contextual learning and memory. In the mammalian hippocampus, LTP can be observed at multiple synaptic pathways after strong stimulation of a single synaptic pathway. This heterosynaptic LTP is believed to involve synaptic tagging of active synapses and capture of plasticity-related proteins that enable heterosynaptic transfer of persistent potentiation. These processes may permit distinct neural pathways to associate information transmitted by separate, but convergent, synaptic inputs. We had previously shown that transcription and epigenetic modifications were necessary for stabilization of homosynaptic LTP. However, it is unclear whether transfer of LTP to a second, heterosynaptic pathway involves b-ARs signalling to the nucleus. Using electrophysiologic recordings in area CA1 of murine hippocampal slices, we show here that pharmacologically inhibiting b-AR activation, transcription, DNA methyltransferase or histone acetyltransferase activation, prevents stabilization of heterosynaptic LTP. Our data suggest that noradrenergic stabilization of heterosynaptic ("tagged") LTP requires not only transcription, but specifically, DNA methylation and histone acetylation. NA promotes stable heterosynaptic plasticity through engagement of nuclear processes that may contribute to prompt consolidation of short-term memories into resilient long-term memories under conditions when the brain's noradrenergic system is recruited.


Assuntos
Região CA1 Hipocampal/fisiologia , Epigênese Genética/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciação de Longa Duração/fisiologia , Norepinefrina/fisiologia , Receptores Adrenérgicos beta/fisiologia , Transdução de Sinais/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Citidina/análogos & derivados , Citidina/farmacologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Histona Acetiltransferases/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propranolol/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
20.
Elife ; 82019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31032799

RESUMO

The thalamocortical synapse of the visual system has been central to our understanding of sensory computations in the cortex. Although we have a fair understanding of the functional properties of the pre and post-synaptic populations, little is known about their synaptic properties, particularly in vivo. We used simultaneous recordings in LGN and V1 in cat in vivo to characterize the dynamic properties of thalamocortical synaptic transmission in monosynaptically connected LGN-V1 neurons. We found that thalamocortical synapses in vivo are unreliable, highly variable and exhibit short-term plasticity. Using biologically constrained models, we found that variable and unreliable synapses serve to increase cortical firing by means of increasing membrane fluctuations, similar to high conductance states. Thus, synaptic variability and unreliability, rather than acting as system noise, do serve a computational function. Our characterization of LGN-V1 synaptic properties constrains existing mathematical models, and mechanistic hypotheses, of a fundamental circuit in computational neuroscience.


Assuntos
Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Tálamo/fisiologia , Córtex Visual/fisiologia , Animais , Gatos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios , Masculino , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Campos Visuais
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