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1.
Nat Commun ; 11(1): 5113, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037215

RESUMO

Striatal activity is dynamically modulated by acetylcholine and dopamine, both of which are essential for basal ganglia function. Synchronized pauses in the activity of striatal cholinergic interneurons (ChINs) are correlated with elevated activity of midbrain dopaminergic neurons, whereas synchronous firing of ChINs induces local release of dopamine. The mechanisms underlying ChIN synchronization and its interplay with dopamine release are not fully understood. Here we show that polysynaptic inhibition between ChINs is a robust network motif and instrumental in shaping the network activity of ChINs. Action potentials in ChINs evoke large inhibitory responses in multiple neighboring ChINs, strong enough to suppress their tonic activity. Using a combination of optogenetics and chemogenetics we show the involvement of striatal tyrosine hydroxylase-expressing interneurons in mediating this inhibition. Inhibition between ChINs is attenuated by dopaminergic midbrain afferents acting presynaptically on D2 receptors. Our results present a novel form of interaction between striatal dopamine and acetylcholine dynamics.


Assuntos
Neurônios Colinérgicos/metabolismo , Corpo Estriado/citologia , Interneurônios/metabolismo , Inibição Neural/fisiologia , Transmissão Sináptica/fisiologia , Acetilcolina/fisiologia , Animais , Condicionamento Clássico , Corpo Estriado/fisiologia , Dopamina , Feminino , Masculino , Mesencéfalo/citologia , Mesencéfalo/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Patch-Clamp , Receptores de Dopamina D2/metabolismo , Recompensa
2.
Nat Commun ; 11(1): 5318, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087709

RESUMO

Synaptic vesicles (SVs) can be pooled across multiple synapses, prompting questions about their dynamic allocation for neurotransmission and plasticity. We find that the axonal traffic of recycling vesicles is not supported by ubiquitous microtubule-based motility but relies on actin instead. Vesicles freed from synaptic clusters undergo ~1 µm bouts of active transport, initiated by nearby elongation of actin filaments. Long distance translocation arises when successive bouts of active transport were linked by periods of free diffusion. The availability of SVs for active transport can be promptly increased by protein kinase A, a key player in neuromodulation. Vesicle motion is in turn impeded by shutting off axonal actin polymerization, mediated by nitric oxide-cyclic GMP signaling leading to inhibition of RhoA. These findings provide a potential framework for coordinating post-and pre-synaptic strength, using retrograde regulation of axonal actin dynamics to mobilize and recruit presynaptic SV resources.


Assuntos
Citoesqueleto de Actina/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Óxido Nítrico/fisiologia , Vesículas Sinápticas/fisiologia , Animais , Transporte Axonal/fisiologia , Transporte Biológico Ativo , Células Cultivadas , GMP Cíclico/fisiologia , Feminino , Hipocampo/citologia , Hipocampo/fisiologia , Proteínas Luminescentes/metabolismo , Masculino , Neurônios/fisiologia , Nocodazol/farmacologia , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/efeitos dos fármacos
3.
Nat Commun ; 11(1): 5369, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097732

RESUMO

GABAA receptors mediate most inhibitory synaptic transmission in the brain of vertebrates. Following GABA binding and fast activation, these receptors undergo a slower desensitization, the conformational pathway of which remains largely elusive. To explore the mechanism of desensitization, we used concatemeric α1ß2γ2 GABAA receptors to selectively introduce gain-of-desensitization mutations one subunit at a time. A library of twenty-six mutant combinations was generated and their bi-exponential macroscopic desensitization rates measured. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. Our work thus hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology.


Assuntos
Sistema Nervoso/metabolismo , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Transmissão Sináptica/fisiologia , Animais , Simulação por Computador , Canais Iônicos , Transporte de Íons , Cinética , Modelos Moleculares , Conformação Molecular , Mutação , Oócitos , Conformação Proteica , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de GABA-A/genética , Xenopus laevis/metabolismo
5.
PLoS One ; 15(9): e0238454, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966302

RESUMO

In this work, we present a local intrinsic rule that we developed, dubbed IP, inspired by the Infomax rule. Like Infomax, this rule works by controlling the gain and bias of a neuron to regulate its rate of fire. We discuss the biological plausibility of the IP rule and compare it to batch normalisation. We demonstrate that the IP rule improves learning in deep networks, and provides networks with considerable robustness to increases in synaptic learning rates. We also sample the error gradients during learning and show that the IP rule substantially increases the size of the gradients over the course of learning. This suggests that the IP rule solves the vanishing gradient problem. Supplementary analysis is provided to derive the equilibrium solutions that the neuronal gain and bias converge to using our IP rule. An analysis demonstrates that the IP rule results in neuronal information potential similar to that of Infomax, when tested on a fixed input distribution. We also show that batch normalisation also improves information potential, suggesting that this may be a cause for the efficacy of batch normalisation-an open problem at the time of this writing.


Assuntos
Aprendizagem/fisiologia , Redes Neurais de Computação , Plasticidade Neuronal/fisiologia , Potenciais de Ação/fisiologia , Algoritmos , Simulação por Computador , Aprendizado Profundo/tendências , Modelos Neurológicos , Modelos Estatísticos , Modelos Teóricos , Neurônios/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia
6.
Nat Commun ; 11(1): 4388, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873805

RESUMO

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found that the protocol that induced t-LTD induced t-LTP. We characterized this form of t-LTP and the mechanisms involved in its induction, as well as that driving this switch from t-LTD to t-LTP. We found that this t-LTP is expressed presynaptically at CA3-CA1 synapses, as witnessed by coefficient of variation, number of failures, paired-pulse ratio and miniature responses analysis. Additionally, this form of presynaptic t-LTP does not require NMDARs but the activation of mGluRs and the entry of Ca2+ into the postsynaptic neuron through L-type voltage-dependent Ca2+ channels and the release of Ca2+ from intracellular stores. Nitric oxide is also required as a messenger from the postsynaptic neuron. Crucially, the release of adenosine and glutamate by astrocytes is required for t-LTP induction and for the switch from t-LTD to t-LTP. Thus, we have discovered a developmental switch of synaptic transmission from t-LTD to t-LTP at hippocampal CA3-CA1 synapses in which astrocytes play a central role and revealed a form of presynaptic LTP and the rules for its induction.


Assuntos
Astrócitos/metabolismo , Hipocampo/crescimento & desenvolvimento , Potenciação de Longa Duração/fisiologia , Transmissão Sináptica/fisiologia , Adenosina/metabolismo , Animais , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Masculino , Camundongos , Técnicas de Patch-Clamp , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
7.
Proc Natl Acad Sci U S A ; 117(33): 20254-20264, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747543

RESUMO

Correlated activation of cortical neurons often occurs in the brain and repetitive correlated neuronal firing could cause long-term modifications of synaptic efficacy and intrinsic excitability. We found that repetitive optogenetic activation of neuronal populations in the mouse cortex caused enhancement of optogenetically evoked firing of local coactivated neurons as well as distant cortical neurons in both ipsilateral and contralateral hemispheres. This global enhancement of evoked responses required coactivation of a sufficiently large population of neurons either within one cortical area or distributed in several areas. Enhancement of neuronal firing was saturable after repeated episodes of coactivation, diminished by inhibition of N-methyl-d-aspartic acid receptors, and accompanied by elevated excitatory postsynaptic potentials, all consistent with activity-induced synaptic potentiation. Chemogenetic inhibition of neuronal activity of the thalamus decreased the enhancement effect, suggesting thalamic involvement. Thus, correlated excitation of large neuronal populations leads to global enhancement of neuronal excitability.


Assuntos
Potenciais de Ação/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Excitabilidade Cortical , Corantes Fluorescentes , Masculino , Camundongos , Rede Nervosa , Transmissão Sináptica/fisiologia
8.
Nat Commun ; 11(1): 4218, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839452

RESUMO

Exposure to social stress and dysregulated serotonergic neurotransmission have both been implicated in the etiology of psychiatric disorders. However, the serotonergic circuit involved in stress vulnerability is still unknown. Here, we explored whether a serotonergic input from the dorsal raphe (DR) to ventral tegmental area (VTA) influences vulnerability to social stress. We identified a distinct, anatomically and functionally defined serotonergic subpopulation in the DR that projects to the VTA (5-HTDR→VTA neurons). Moreover, we found that susceptibility to social stress decreased the firing activity of 5-HTDR→VTA neurons. Importantly, the bidirectional manipulation of 5-HTDR→VTA neurons could modulate susceptibility to social stress. Our findings reveal that the activity of 5-HTDR→VTA neurons may be an essential factor in determining individual levels of susceptibility to social stress and suggest that targeting specific serotonergic circuits may aid the development of therapies for the treatment of stress-related disorders.


Assuntos
Núcleo Dorsal da Rafe/fisiologia , Vias Neurais/fisiologia , Neurônios Serotoninérgicos/fisiologia , Estresse Psicológico/fisiopatologia , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Núcleo Dorsal da Rafe/citologia , Núcleo Dorsal da Rafe/metabolismo , Ácido Glutâmico/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Neurônios Serotoninérgicos/citologia , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/metabolismo
9.
Neuron ; 107(4): 667-683.e9, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32616470

RESUMO

Presynaptic CaV2 channels are essential for Ca2+-triggered exocytosis. In addition, there are two competing models for their roles in synapse structure. First, Ca2+ channels or Ca2+ entry may control synapse assembly. Second, active zone proteins may scaffold CaV2s to presynaptic release sites, and synapse structure is CaV2 independent. Here, we ablated all three CaV2s using conditional knockout in cultured hippocampal neurons or at the calyx of Held, which abolished evoked exocytosis. Compellingly, synapse and active zone structure, vesicle docking, and transsynaptic nano-organization were unimpaired. Similarly, long-term blockade of action potentials and Ca2+ entry did not disrupt active zone assembly. Although CaV2 knockout impaired the localization of ß subunits, α2δ-1 localized normally. Rescue with CaV2 restored exocytosis, and CaV2 active zone targeting depended on the intracellular C-terminus. We conclude that synapse assembly is independent of CaV2s or Ca2+ entry through them. Instead, active zone proteins recruit and anchor CaV2s via CaV2 C-termini.


Assuntos
Canais de Cálcio/metabolismo , Terminações Pré-Sinápticas/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Animais , Cálcio/metabolismo , Canais de Cálcio/genética , Exocitose/fisiologia , Camundongos Knockout , Neurônios/metabolismo , Vesículas Sinápticas/metabolismo
10.
Proc Natl Acad Sci U S A ; 117(25): 14493-14502, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513685

RESUMO

A high rate of synaptic vesicle (SV) release is required at cerebellar mossy fiber terminals for rapid information processing. As the number of release sites is limited, fast SV reloading is necessary to achieve sustained release. However, rapid reloading has not been observed directly. Here, we visualize SV movements near presynaptic membrane using total internal reflection fluorescence (TIRF) microscopy. Upon stimulation, SVs appeared in the TIRF-field and became tethered to the presynaptic membrane with unexpectedly rapid time course, almost as fast as SVs disappeared due to release. However, such stimulus-induced tethering was abolished by inhibiting exocytosis, suggesting that the tethering is tightly coupled to preceding exocytosis. The newly tethered vesicles became fusion competent not immediately but only 300 ms to 400 ms after tethering. Together with model simulations, we propose that rapid tethering leads to an immediate filling of vacated spaces and release sites within <100 nm of the active zone by SVs, which serve as precursors of readily releasable vesicles, thereby shortening delays during sustained activity.


Assuntos
Cerebelo/fisiologia , Modelos Neurológicos , Fibras Nervosas/metabolismo , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/metabolismo , Animais , Cerebelo/citologia , Exocitose/fisiologia , Feminino , Microscopia Intravital , Masculino , Microscopia de Fluorescência , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/metabolismo , Ratos , Wisteria
11.
Proc Natl Acad Sci U S A ; 117(25): 14503-14511, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513712

RESUMO

The nanoscale co-organization of neurotransmitter receptors facing presynaptic release sites is a fundamental determinant of their coactivation and of synaptic physiology. At excitatory synapses, how endogenous AMPARs, NMDARs, and mGluRs are co-organized inside the synapse and their respective activation during glutamate release are still unclear. Combining single-molecule superresolution microscopy, electrophysiology, and modeling, we determined the average quantity of each glutamate receptor type, their nanoscale organization, and their respective activation. We observed that NMDARs form a unique cluster mainly at the center of the PSD, while AMPARs segregate in clusters surrounding the NMDARs. mGluR5 presents a different organization and is homogenously dispersed at the synaptic surface. From these results, we build a model predicting the synaptic transmission properties of a unitary synapse, allowing better understanding of synaptic physiology.


Assuntos
Modelos Neurológicos , Neurônios/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia , Animais , Células Cultivadas , Embrião de Mamíferos , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/citologia , Hipocampo/diagnóstico por imagem , Hipocampo/fisiologia , Microscopia Intravital , Neurônios/ultraestrutura , Técnicas de Patch-Clamp , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Imagem Individual de Molécula
12.
Nat Neurosci ; 23(8): 968-980, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32541962

RESUMO

The ventral tegmental area (VTA) is important for reward processing and motivation. The anatomic organization of neurotransmitter-specific inputs to the VTA remains poorly resolved. In the present study, we mapped the major neurotransmitter projections to the VTA through cell-type-specific retrograde and anterograde tracing. We found that glutamatergic inputs arose from a variety of sources and displayed some connectivity biases toward specific VTA cell types. The sources of GABAergic projections were more widespread, displayed a high degree of differential innervation of subregions in the VTA and were largely biased toward synaptic contact with local GABA neurons. Inactivation of GABA release from the two major sources, locally derived versus distally derived, revealed distinct roles for these projections in behavioral regulation. Optogenetic manipulation of individual distal GABAergic inputs also revealed differential behavioral effects. These results demonstrate that GABAergic projections to the VTA are a major contributor to the regulation and diversification of the structure.


Assuntos
Neurônios GABAérgicos/metabolismo , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/metabolismo , Animais , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Neurônios Dopaminérgicos/fisiologia , Medo/fisiologia , Feminino , Masculino , Camundongos , Atividade Motora/fisiologia , Vias Neurais/metabolismo , Optogenética , Recompensa , Autoestimulação
13.
Nat Neurosci ; 23(8): 908-917, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32541963

RESUMO

A group of neurons can generate patterns of activity that represent information about stimuli; subsequently, the group can transform and transmit activity patterns across synapses to spatially distributed areas. Recent studies in neuroscience have begun to independently address the two components of information processing: the representation of stimuli in neural activity and the transmission of information in networks that model neural interactions. Yet only recently are studies seeking to link these two types of approaches. Here we briefly review the two separate bodies of literature; we then review the recent strides made to address this gap. We continue with a discussion of how patterns of activity evolve from one representation to another, forming dynamic representations that unfold on the underlying network. Our goal is to offer a holistic framework for understanding and describing neural information representation and transmission while revealing exciting frontiers for future research.


Assuntos
Encéfalo/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Transmissão Sináptica/fisiologia , Animais , Cognição/fisiologia , Humanos , Redes Neurais de Computação
14.
J Neurosci ; 40(28): 5389-5401, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32532887

RESUMO

Spontaneous neurotransmitter release is a fundamental property of synapses in which neurotransmitter filled vesicles release their content independent of presynaptic action potentials (APs). Despite their seemingly random nature, these spontaneous fusion events can be regulated by Ca2+ signaling pathways. Here, we probed the mechanisms that maintain Ca2+ sensitivity of spontaneous release events in synapses formed between hippocampal neurons cultured from rats of both sexes. In this setting, we examined the potential role of vesicle-associated membrane protein 4 (VAMP4), a vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein in spontaneous neurotransmission. Our results show that VAMP4 is required for Ca2+-dependent spontaneous excitatory neurotransmission, with a limited role in spontaneous inhibitory neurotransmission. Key residues in VAMP4 that regulate its retrieval as well as functional clathrin-mediated vesicle trafficking were essential for the maintenance of VAMP4-mediated spontaneous release. Moreover, high-frequency stimulation (HFS) that typically triggers asynchronous release and retrieval of VAMP4 from the plasma membrane also augmentsCa2+-sensitive spontaneous release for up to 30 min in a VAMP4-dependent manner. This VAMP4-mediated link between asynchronous and spontaneous excitatory neurotransmission might serve as a presynaptic substrate for synaptic plasticity coupling distinct forms of release.SIGNIFICANCE STATEMENT Spontaneous neurotransmitter release that occurs independent of presynaptic action potentials (APs) shows significant sensitivity to intracellular Ca2+ levels. In this study, we identify the vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) molecule vesicle-associated membrane protein 4 (VAMP4) as a key component of the machinery that maintains these Ca2+-sensitive fraction of spontaneous release events. Following brief intense activity, VAMP4-dependent synaptic vesicle retrieval supports a pool of vesicles that fuse spontaneously in the long term. We propose that this vesicle trafficking pathway acts to shape spontaneous release and associated signaling based on previous activity history of synapses.


Assuntos
Cálcio/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Proteínas R-SNARE/metabolismo , Vesículas Sinápticas/metabolismo , Potenciais de Ação/fisiologia , Animais , Células Cultivadas , Feminino , Hipocampo/citologia , Masculino , Camundongos , Neurônios/citologia , Técnicas de Patch-Clamp , Proteínas R-SNARE/genética , Ratos , Ratos Sprague-Dawley , Sinapses/metabolismo , Transmissão Sináptica/fisiologia
15.
PLoS One ; 15(4): e0232451, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353050

RESUMO

Numerous neuronal properties including the synaptic vesicle release process, neurotransmitter receptor complement, and postsynaptic ion channels are involved in transforming synaptic inputs into postsynaptic spiking. Temperature is a significant influencer of neuronal function and synaptic integration. Changing temperature can affect neuronal physiology in a diversity of ways depending on how it affects different members of the cell's ion channel complement. Temperature's effects on neuronal function are critical for pathological states such as fever, which can trigger seizure activity, but are also important in interpreting and comparing results of experiments conducted at room vs physiological temperature. The goal of this study was to examine the influence of temperature on synaptic properties and ion channel function in thalamocortical (TC) relay neurons in acute brain slices of the dorsal lateral geniculate nucleus, a key synaptic target of retinal ganglion cells in the thalamus. Warming the superfusate in patch clamp experiments with acutely-prepared brain slices led to an overall inhibition of synaptically-driven spiking behavior in TC neurons in response to a retinal ganglion cell spike train. Further study revealed that this was associated with an increase in presynaptic synaptic vesicle release probability and synaptic depression and altered passive and active membrane properties. Additionally, warming the superfusate triggered activation of an inwardly rectifying potassium current and altered the voltage-dependence of voltage-gated Na+ currents and T-type calcium currents. This study highlights the importance of careful temperature control in ex vivo physiological experiments and illustrates how numerous properties such as synaptic inputs, active conductances, and passive membrane properties converge to determine spike output.


Assuntos
Corpos Geniculados/fisiologia , Temperatura Alta/efeitos adversos , Optogenética/métodos , Terminações Pré-Sinápticas/fisiologia , Células Ganglionares da Retina/fisiologia , Potenciais de Ação/fisiologia , Animais , Canais de Cálcio Tipo T/metabolismo , Feminino , Corpos Geniculados/citologia , Masculino , Camundongos , Técnicas de Patch-Clamp , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Transmissão Sináptica/fisiologia , Canais de Sódio Disparados por Voltagem/metabolismo
16.
Nat Commun ; 11(1): 2674, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471987

RESUMO

Increasing evidence indicates that guidance molecules used during development for cellular and axonal navigation also play roles in synapse maturation and homeostasis. In C. elegans the netrin receptor UNC-40/DCC controls the growth of dendritic-like muscle cell extensions towards motoneurons and is required to recruit type A GABA receptors (GABAARs) at inhibitory neuromuscular junctions. Here we show that activation of UNC-40 assembles an intracellular synaptic scaffold by physically interacting with FRM-3, a FERM protein orthologous to FARP1/2. FRM-3 then recruits LIN-2, the ortholog of CASK, that binds the synaptic adhesion molecule NLG-1/Neuroligin and physically connects GABAARs to prepositioned NLG-1 clusters. These processes are orchestrated by the synaptic organizer CePunctin/MADD-4, which controls the localization of GABAARs by positioning NLG-1/neuroligin at synapses and regulates the synaptic content of GABAARs through the UNC-40-dependent intracellular scaffold. Since DCC is detected at GABA synapses in mammals, DCC might also tune inhibitory neurotransmission in the mammalian brain.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Moléculas de Adesão Celular/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de GABA-A/metabolismo , Transmissão Sináptica/fisiologia , Animais , Orientação de Axônios/fisiologia , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas de Helminto/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Junção Neuromuscular/metabolismo , Sinapses/fisiologia
17.
J Neurosci ; 40(25): 4824-4841, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32414783

RESUMO

VGCCs are multisubunit complexes that play a crucial role in neuronal signaling. Auxiliary α2δ subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming α1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of α2δ subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism, and epilepsy. However, the contribution of distinct α2δ subunits to excitatory/inhibitory imbalance and aberrant network connectivity characteristic for these pathologic conditions remains unclear. Here, we show that α2δ1 overexpression enhances spontaneous neuronal network activity in developing and mature cultures of hippocampal neurons. In contrast, overexpression, but not downregulation, of α2δ3 enhances neuronal firing in immature cultures, whereas later in development it suppresses neuronal activity. We found that α2δ1 overexpression increases excitatory synaptic density and selectively enhances presynaptic glutamate release, which is impaired on α2δ1 knockdown. Overexpression of α2δ3 increases the excitatory synaptic density as well but also facilitates spontaneous GABA release and triggers an increase in the density of inhibitory synapses, which is accompanied by enhanced axonaloutgrowth in immature interneurons. Together, our findings demonstrate that α2δ1 and α2δ3 subunits play distinct but complementary roles in driving formation of structural and functional network connectivity during early development. An alteration in α2δ surface expression during critical developmental windows can therefore play a causal role and have a profound impact on the excitatory-to-inhibitory balance and network connectivity.SIGNIFICANCE STATEMENT The computational capacity of neuronal networks is determined by their connectivity. Chemical synapses are the main interface for transfer of information between individual neurons. The initial formation of network connectivity requires spontaneous electrical activity and the calcium channel-mediated signaling. We found that, in early development, auxiliary α2δ3 subunits of calcium channels foster presynaptic release of GABA, trigger formation of inhibitory synapses, and promote axonal outgrowth in inhibitory interneurons. In contrast, later in development, α2δ1 subunits promote the glutamatergic neurotransmission and synaptogenesis, as well as strongly enhance neuronal network activity. We propose that formation of connectivity in neuronal networks is associated with a concerted interplay of α2δ1 and α2δ3 subunits of calcium channels.


Assuntos
Canais de Cálcio/metabolismo , Hipocampo/fisiologia , Rede Nervosa/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Células HEK293 , Humanos , Camundongos , Ratos , Transmissão Sináptica/fisiologia
18.
J Neurosci ; 40(25): 4858-4880, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32424020

RESUMO

Heightened aggression can be serious concerns for the individual and society at large and are symptoms of many psychiatric illnesses, such as post-traumatic stress disorder. The circuit and synaptic mechanisms underlying experience-induced aggression increase, however, are poorly understood. Here we find that prior attack experience leading to an increase in aggressive behavior, known as aggression priming, activates neurons within the posterior ventral segment of the medial amygdala (MeApv). Optogenetic stimulation of MeApv using a synaptic depression protocol suppresses aggression priming, whereas high-frequency stimulation enhances aggression, mimicking attack experience. Interrogation of the underlying neural circuitry revealed that the MeApv mediates aggression priming via synaptic connections with the ventromedial hypothalamus (VmH) and bed nucleus of the stria terminalis (BNST). These pathways undergo NMDAR-dependent synaptic potentiation after attack. Furthermore, we find that the MeApv-VmH synapses selectively control attack duration, whereas the MeApv-BNST synapses modulate attack frequency, both with no effect on social behavior. Synaptic potentiation of the MeApv-VmH and MeApv-BNST pathways contributes to increased aggression induced by traumatic stress, and weakening synaptic transmission at these synapses blocks the effect of traumatic stress on aggression. These results reveal a circuit and synaptic basis for aggression modulation by experience that can be potentially leveraged toward clinical interventions.SIGNIFICANCE STATEMENT Heightened aggression can have devastating social consequences and may be associated with psychiatric disorders, such as post-traumatic stress disorder. The circuit and synaptic mechanisms underlying experience-induced aggression escalation, however, are poorly understood. Here we identify two aggression pathways between the posterior ventral segment of the medial amygdala and its downstream synaptic partners, the ventromedial hypothalamus and bed nucleus of the stria terminalis that undergo synaptic potentiation after attack and traumatic stress to enhance aggression. Notably, weakening synaptic transmission in these circuits blocks aggression priming, naturally occurring aggression, and traumatic stress-induced aggression increase. These results illustrate a circuit and synaptic basis of aggression modulation by experience, which can be potentially targeted for clinical interventions.


Assuntos
Agressão/fisiologia , Complexo Nuclear Corticomedial/fisiologia , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Angústia Psicológica
19.
J Neurosci ; 40(25): 4881-4887, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32430298

RESUMO

Understanding how disruption of prefrontal cortex (PFC) maturation during adolescence is crucial to reveal which neural processes could contribute to the onset of psychiatric disorders that display frontal cortical deficits. Of particular interest is the gain of GABAergic function in the PFC during adolescence and its susceptibility to the impact of transient blockade of NMDA receptor function. Here we assessed whether exposure to MK-801 during adolescence in male rats triggers a state of excitatory-inhibitory imbalance in the PFC that limits its functional capacity to regulate behavior in adulthood. Recordings from PFC brain slices revealed that MK-801 exposure during adolescence preferentially reduces the presynaptic functionality of GABAergic activity over that of excitatory synapses. As a result, an imbalance of excitatory-inhibitory synaptic activity emerges in the PFC that correlates linearly with the GABAergic deficit. Notably, the data also suggest that the diminished prefrontal GABAergic function could arise from a deficit in the recruitment of fast-spiking interneurons by excitatory inputs during adolescence. At the behavioral level, MK-801 exposure during adolescence did not disrupt the acquisition of trace fear conditioning, but markedly increased the level of freezing response during extinction testing. Infusion of the GABAA receptor-positive allosteric modulator Indiplon into the PFC before extinction testing reduced the level of freezing response in MK-801-treated rats to control levels. Collectively, the results indicate NMDA receptor signaling during adolescence enables the gain of prefrontal GABAergic function, which is required for maintaining proper excitatory-inhibitory balance in the PFC and its control of behavioral responses.SIGNIFICANCE STATEMENT A developmental disruption of prefrontal cortex maturation has been implicated in the pathophysiology of cognitive deficits in psychiatric disorders. Of particular interest is the susceptibility of the local GABAergic circuit to the impact of transient disruption of NMDA receptors. Here we found that NMDA receptor signaling is critical to enable the gain of prefrontal GABAergic transmission during adolescence for maintaining proper levels of excitatory-inhibitory balance in the PFC and its control of behavior.


Assuntos
Medo/fisiologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia , Animais , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos
20.
J Neurosci ; 40(24): 4700-4714, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32376778

RESUMO

Phase locking of auditory-nerve-fiber (ANF) responses to the temporal fine structure of acoustic stimuli, a hallmark of the auditory system's temporal precision, is important for many aspects of hearing. Previous work has shown that phase-locked period histograms are often well described by exponential transfer functions relating instantaneous stimulus pressure to instantaneous spike rate, with no observed clipping of the histograms. The operating points and slopes of these functions change with stimulus level. The mechanism underlying this apparent gain control is unclear but is distinct from mechanical compression, is independent of refractoriness and spike-rate adaptation, and is apparently instantaneous. Here we show that these findings can be accounted for by a model consisting of a static Boltzmann transducer function yielding a clipped output, followed by a lowpass filter and a static exponential transfer function. Using responses to tones of ANFs from cats of both sexes, we show that, for a given ANF, the period histograms obtained at all stimulus levels for a given stimulus frequency can be described using one set of level-independent model parameters. The model also accounts for changes in the maximum and minimum instantaneous spike rates with changes in stimulus level. Notably, the estimated cutoff frequency is lower for low- than for high-spontaneous-rate ANFs, implying a synapse-specific contribution to lowpass filtering. These findings advance our understanding of ANF phase locking by highlighting the role of peripheral filtering mechanisms in shaping responses of individual ANFs.SIGNIFICANCE STATEMENT Phase locking of auditory-nerve-fiber responses to the temporal fine structure of acoustic stimuli is important for many aspects of hearing. Period histograms typically retain an approximately sinusoidal shape across stimulus levels, with the peripheral auditory system operating as though its overall transfer function is an exponential function whose slope decreases with increasing stimulus level. This apparent gain control can be accounted for by a static saturating transducer function followed by a lowpass filter. In addition to attenuating the AC component, the filter approximately recovers the sinusoidal waveform of the stimulus. The estimated cutoff frequency varies with spontaneous rate, revealing a synaptic contribution to lowpass filtering. These findings highlight the significant impact of peripheral filtering mechanisms on phase locking.


Assuntos
Vias Auditivas/fisiologia , Nervo Coclear/fisiologia , Células Ciliadas Auditivas/fisiologia , Modelos Neurológicos , Transmissão Sináptica/fisiologia , Estimulação Acústica , Animais , Gatos , Potenciais Evocados Auditivos/fisiologia , Feminino , Masculino
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