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1.
Proc Natl Acad Sci U S A ; 119(32): e2116895119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35925891

RESUMO

Diverse interneuron subtypes shape sensory processing in mature cortical circuits. During development, sensory deprivation evokes powerful synaptic plasticity that alters circuitry, but how different inhibitory subtypes modulate circuit dynamics in response to this plasticity remains unclear. We investigate how deprivation-induced synaptic changes affect excitatory and inhibitory firing rates in a microcircuit model of the sensory cortex with multiple interneuron subtypes. We find that with a single interneuron subtype (parvalbumin-expressing [PV]), excitatory and inhibitory firing rates can only be comodulated-increased or decreased together. To explain the experimentally observed independent modulation, whereby one firing rate increases and the other decreases, requires strong feedback from a second interneuron subtype (somatostatin-expressing [SST]). Our model applies to the visual and somatosensory cortex, suggesting a general mechanism across sensory cortices. Therefore, we provide a mechanistic explanation for the differential role of interneuron subtypes in regulating firing rates, contributing to the already diverse roles they serve in the cortex.


Assuntos
Interneurônios , Modelos Neurológicos , Plasticidade Neuronal , Privação Sensorial , Animais , Interneurônios/fisiologia , Parvalbuminas/metabolismo , Córtex Somatossensorial/fisiologia , Córtex Visual/fisiologia
2.
Nat Neurosci ; 25(8): 1049-1058, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35915179

RESUMO

Mammalian neocortical neurons span one of the most diverse cell type spectra of any tissue. Cortical neurons are born during embryonic development, and their maturation extends into postnatal life. The regulatory strategies underlying progressive neuronal development and maturation remain unclear. Here we present an integrated single-cell epigenomic and transcriptional analysis of individual mouse and marmoset cortical neuron classes, spanning both early postmitotic stages of identity acquisition and later stages of neuronal plasticity and circuit integration. We found that, in both species, the regulatory strategies controlling early and late stages of pan-neuronal development diverge. Early postmitotic neurons use more widely shared and evolutionarily conserved molecular regulatory programs. In contrast, programs active during later neuronal maturation are more brain- and neuron-specific and more evolutionarily divergent. Our work uncovers a temporal shift in regulatory choices during neuronal diversification and maturation in both mice and marmosets, which likely reflects unique evolutionary constraints on distinct events of neuronal development in the neocortex.


Assuntos
Neocórtex , Animais , Callithrix , Mamíferos , Camundongos , Neurogênese/fisiologia , Plasticidade Neuronal , Neurônios/fisiologia
3.
Proc Natl Acad Sci U S A ; 119(32): e2203883119, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914168

RESUMO

L-type CaV1.3 calcium channels are expressed on the dendrites and soma of neurons, and there is a paucity of information about its role in hippocampal plasticity. Here, by genetic targeting to ablate CaV1.3 RNA editing, we demonstrate that unedited CaV1.3ΔECS mice exhibited improved learning and enhanced long-term memory, supporting a functional role of RNA editing in behavior. Significantly, the editing paradox that functional recoding of CaV1.3 RNA editing sites slows Ca2+-dependent inactivation to increase Ca2+ influx but reduces channel open probability to decrease Ca2+ influx was resolved. Mechanistically, using hippocampal slice recordings, we provide evidence that unedited CaV1.3 channels permitted larger Ca2+ influx into the hippocampal pyramidal neurons to bolster neuronal excitability, synaptic transmission, late long-term potentiation, and increased dendritic arborization. Of note, RNA editing of the CaV1.3 IQ-domain was found to be evolutionarily conserved in mammals, which lends support to the importance of the functional recoding of the CaV1.3 channel in brain function.


Assuntos
Canais de Cálcio Tipo L , Edição de RNA , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Hipocampo/metabolismo , Mamíferos/metabolismo , Camundongos , Plasticidade Neuronal/genética , Neurônios/metabolismo , Células Piramidais/metabolismo
4.
Neural Plast ; 2022: 6472475, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35915650

RESUMO

Low-intensity focused ultrasound (LIFU) is a potential noninvasive method to alleviate allodynia by modulating the central nervous system. However, the underlying analgesic mechanisms remain unexplored. Here, we assessed how LIFU at the anterior cingulate cortex (ACC) affects behavior response and central plasticity resulting from chronic constrictive injury (CCI). The safety of LIFU stimulation was assessed by hematoxylin and eosin (H&E) and Fluoro-Jade C (FJC) staining. A 21-day ultrasound exposure therapy was conducted from day 91 after CCI surgery in mice. We assessed the 50% mechanical withdrawal threshold (MWT50) using Von Frey filaments (VFFs). The expression levels of microtubule-associated protein 2 (MAP2), growth-associated protein 43 (GAP43), and tau were determined via western blotting (WB) and immunofluorescence (IF) staining to evaluate the central plasticity in ACC. The regions of ACC were activated effectively and safely by LIFU stimulation, which significantly increased the number of c-fos-positive cells (P < 0.05) with no bleeding, coagulative necrosis, and neuronal loss. Under chronic neuropathic pain- (CNP-) induced allodynia, MWT50 decreased significantly (P < 0.05), and overexpression of MAP2, GAP43, and tau was also observed. After 3 weeks of treatment, significant increases in MWT50 were found in the CCI+LIFU group compared with the CCI group (P < 0.05). WB and IF staining both demonstrated a significant reduction in the expression levels of MAP2, GAP43, and tau (P < 0.05). LIFU treatment on ACC can effectively attenuate CNP-evoked mechanical sensitivity to pain and reverse aberrant central plasticity.


Assuntos
Hiperalgesia , Neuralgia , Animais , Giro do Cíngulo/metabolismo , Hiperalgesia/metabolismo , Hiperalgesia/terapia , Camundongos , Neuralgia/metabolismo , Neuralgia/terapia , Plasticidade Neuronal , Ratos , Ratos Sprague-Dawley
5.
Neural Plast ; 2022: 6771999, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35915651

RESUMO

There is compelling evidence from animal models that physical exercise can enhance visual cortex neuroplasticity. In this narrative review, we explored whether exercise has the same effect in humans. We found that while some studies report evidence consistent with exercise-induced enhancement of human visual cortex neuroplasticity, others report no effect or even reduced neuroplasticity following exercise. Differences in study methodology may partially explain these varying results. Because the prospect of exercise increasing human visual cortex neuroplasticity has important implications for vision rehabilitation, additional research is required to resolve this discrepancy in the literature.


Assuntos
Plasticidade Neuronal , Córtex Visual , Animais , Exercício Físico , Terapia por Exercício , Humanos
6.
Cell Rep ; 40(5): 111151, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35926462

RESUMO

Serial section electron microscopy (ssEM) can provide comprehensive 3D ultrastructural information of the brain with exceptional computational cost. Targeted reconstruction of subcellular structures from ssEM datasets is less computationally demanding but still highly informative. We thus developed a region-CNN-based deep learning method to identify, segment, and reconstruct synapses and mitochondria to explore the structural plasticity of synapses and mitochondria in the auditory cortex of mice subjected to fear conditioning. Upon reconstructing over 135,000 mitochondria and 160,000 synapses, we find that fear conditioning significantly increases the number of mitochondria but decreases their size and promotes formation of multi-contact synapses, comprising a single axonal bouton and multiple postsynaptic sites from different dendrites. Modeling indicates that such multi-contact configuration increases the information storage capacity of new synapses by over 50%. With high accuracy and speed in reconstruction, our method yields structural and functional insight into cellular plasticity associated with fear learning.


Assuntos
Aprendizado Profundo , Animais , Medo , Camundongos , Microscopia Eletrônica , Mitocôndrias/ultraestrutura , Plasticidade Neuronal , Sinapses/metabolismo
7.
Annu Rev Neurosci ; 45: 151-175, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35803588

RESUMO

The cerebellar cortex is an important system for relating neural circuits and learning. Its promise reflects the longstanding idea that it contains simple, repeated circuit modules with only a few cell types and a single plasticity mechanism that mediates learning according to classical Marr-Albus models. However, emerging data have revealed surprising diversity in neuron types, synaptic connections, and plasticity mechanisms, both locally and regionally within the cerebellar cortex. In light of these findings, it is not surprising that attempts to generate a holistic model of cerebellar learning across different behaviors have not been successful. While the cerebellum remains an ideal system for linking neuronal function with behavior, it is necessary to update the cerebellar circuit framework to achieve its great promise. In this review, we highlight recent advances in our understanding of cerebellar-cortical cell types, synaptic connections, signaling mechanisms, and forms of plasticity that enrich cerebellar processing.


Assuntos
Plasticidade Neuronal , Células de Purkinje , Córtex Cerebelar/fisiologia , Cerebelo , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Células de Purkinje/fisiologia
8.
Annu Rev Neurosci ; 45: 471-489, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35803589

RESUMO

Unimodal sensory loss leads to structural and functional changes in both deprived and nondeprived brain circuits. This process is broadly known as cross-modal plasticity. The evidence available indicates that cross-modal changes underlie the enhanced performances of the spared sensory modalities in deprived subjects. Sensory experience is a fundamental driver of cross-modal plasticity, yet there is evidence from early-visually deprived models supporting an additional role for experience-independent factors. These experience-independent factors are expected to act early in development and constrain neuronal plasticity at later stages. Here we review the cross-modal adaptations elicited by congenital or induced visual deprivation prior to vision. In most of these studies, cross-modal adaptations have been addressed at the structural and functional levels. Here, we also appraise recent data regarding behavioral performance in early-visually deprived models. However, further research is needed to explore how circuit reorganization affects their function and what brings about enhanced behavioral performance.


Assuntos
Plasticidade Neuronal , Privação Sensorial , Encéfalo , Humanos , Plasticidade Neuronal/fisiologia , Privação Sensorial/fisiologia , Visão Ocular
9.
Sci Rep ; 12(1): 11610, 2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35803955

RESUMO

Neural networks tune synaptic and cellular properties to produce stable activity. One form of homeostatic regulation involves scaling the strength of synapses up or down in a global and multiplicative manner to oppose activity disturbances. In American bullfrogs, excitatory synapses scale up to regulate breathing motor function after inactivity in hibernation, connecting homeostatic compensation to motor behavior. In traditional models of homeostatic synaptic plasticity, inactivity is thought to increase synaptic strength via mechanisms that involve reduced Ca2+ influx through voltage-gated channels. Therefore, we tested whether pharmacological inactivity and inhibition of voltage-gated Ca2+ channels are sufficient to drive synaptic compensation in this system. For this, we chronically exposed ex vivo brainstem preparations containing the intact respiratory network to tetrodotoxin (TTX) to stop activity and nimodipine to block L-type Ca2+ channels. We show that hibernation and TTX similarly increased motoneuron synaptic strength and that hibernation occluded the response to TTX. In contrast, inhibiting L-type Ca2+ channels did not upregulate synaptic strength but disrupted the apparent multiplicative scaling of synaptic compensation typically observed in response to hibernation. Thus, inactivity drives up synaptic strength through mechanisms that do not rely on reduced L-type channel function, while Ca2+ signaling associated with the hibernation environment independently regulates the balance of synaptic weights. Altogether, these results point to multiple feedback signals for shaping synaptic compensation that gives rise to proper network function during environmental challenges in vivo.


Assuntos
Hibernação , Animais , Neurônios Motores/fisiologia , Plasticidade Neuronal/fisiologia , Rana catesbeiana , Sinapses/fisiologia , Tetrodotoxina/farmacologia
10.
Cells ; 11(13)2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35805118

RESUMO

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition which develops either due to stress or witnessing a traumatic situation. PTSD is characterized by acute and chronic stress response exhibit anxiety, fear, and an increased inflammatory etiology. Inflammation contributes a critical role in several parts of the brain that control fear and flashback cognatic function. It is known that impairment of the neurological circuit leads to the development of PTSD. Evidence has suggested that dysregulation of the sympathetic nervous system and hypothalamic-pituitary adrenal (HPA) axis and inflammatory responsiveness are pivotal and a greater risk in PTSD. NF-κB, a master regulator for inflammation, has been showed to modulate memory reconsolidation and synaptic plasticity; however, NF-κB's association with PTSD remain elusive. In this review, we provide relevant findings regarding NF-κB activity in various components of brain and describe a potential mechanism linking PTSD using preclinical and clinical models. We envisage NF-κB signaling as a crucial mediator for inflammation, cognitive function, memory restoration and behavioral actions of stress and suggest that it could be used for therapeutic intervention in PTSD.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Humanos , Inflamação/complicações , NF-kappa B , Plasticidade Neuronal , Sistema Hipófise-Suprarrenal , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/psicologia
11.
Nihon Yakurigaku Zasshi ; 157(4): 244-247, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-35781453

RESUMO

Brain injury causes temporary or permanent impairment of brain function due to an accident or circulation disorders. Even after rehabilitation training, there are often persistent functional impairments. Recent advances in our understanding of the repair mechanisms of neural circuits after brain injury have led to the possibility that these mechanisms may offer potential therapeutic targets for drugs that promote functional recovery after brain injury. Neuroplasticity is believed to be important for the recovery process after brain injury in the brain regions associated with injured region for compensation. The effectiveness of drugs for restoring brain function after stroke investigated in a variety of animal models and clinical trials has been focused on drugs that act on the monoamine system to modulate neuroplasticity, as well as other targets such as NMDA receptors and CCR5. Recently, we focused on novel small compound, edonerpic maleate, as a drug which facilitates experience-dependent synaptic delivery of AMPA receptor. We found that edonerpic maleate binds to Collapsin-response mediator protein 2, a downstream molecule of Semaphorin and enhance synaptic plasticity by facilitating synaptic delivery of AMPA receptors, thereby promoting functional recovery in a rehabilitation-dependent manner after brain injury in rodents and non-human primates. Further investigations is needed to seek more appropriate drug targets from both preclinical animal studies and clinical trials, and to translate preclinical results into successful clinical trials.


Assuntos
Lesões Encefálicas , Fármacos Neuroprotetores , Animais , Encéfalo , Lesões Encefálicas/reabilitação , Maleatos/farmacologia , Maleatos/uso terapêutico , Plasticidade Neuronal/fisiologia , Recuperação de Função Fisiológica/fisiologia
13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 38(7): 625-631, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-35786457

RESUMO

Objective To investigate the effect of Fasudil on H2O2-induced apoptosis and synaptic plasticity in human neuroblastoma SY5Y cells and its mechanism. Methods The cells were divided into three groups: PBS control group, H2O2 model group (250 µmol/L H2O2 treatment) and Fasudil intervention group (250 µmol/L H2O2 combined with 15 µg/mL Fasudil treatment). MTT assay was applied to detect cell activity and TUNEL was performed to detect cell apoptosis respectively. Immunofluorescence cytochemical staining was used to determine the expression of neurite outgrowth inhibitor A (NogoA), Nogo receptor (NgR) and synaptophysin (Syn). Western blotting was then conducted to detect the expression of NogoA, NgR, p75 neurotrophin receptor (p75NTR), leucine-rich repeat Ig domain-containing Nogo-interacting protein 1 (LINGO-1), Syn and postsynaptic density protein-95 (PSD-95). Results Compared with the PBS group, the H2O2 group showed decreased cell viability and increased apoptosis rate while Fasudil treatment significantly increased the cell viability and reduced the apoptosis rate. Compared with the H2O2 model group, Fasudil intervention increased expressions of Syn and PSD-95. Compared with the PBS group, the expression of NogoA and its receptor complex NgR/p75NTR/LINGO-1 grew significantly in the H2O2 group, suggesting Fasudil treatment could inhibit the expression of NogoA and its receptor complex NgR/p75NTR/LINGO-1. Conclusion Fasudil may inhibit the activation of the NogoA/NgR signaling pathway, therefore reducing the apoptosis induced by H2O2 in SH-SY5Y cells and enhancing the plasticity of the synapses.


Assuntos
Neuroblastoma , Receptores Nogo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Apoptose , Humanos , Peróxido de Hidrogênio/farmacologia , Crescimento Neuronal , Plasticidade Neuronal , Receptor Nogo 1 , Receptor de Fator de Crescimento Neural , Transdução de Sinais
14.
Int J Mol Sci ; 23(13)2022 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-35806103

RESUMO

In ADHD treatment, methylphenidate (MPH) is the most frequently used medication. The present work provides evidence that MPH restored behavioral impairments and neuroplasticity due to changes in AMPAR subunit composition and distribution, as well as maturation of dendritic spines, in a prenatal nicotine exposure (PNE) ADHD mouse model. PNE animals and controls were given a single oral dose of MPH (1 mg/kg), and their behavior was tested for attention, hyperactivity, and working memory. Long-term potentiation (LTP) was induced and analyzed at the CA3/CA1 synapse in hippocampal slices taken from the same animals tested behaviorally, measuring fEPSPs and whole-cell patch-clamp EPSCs. By applying crosslinking and Western blots, we estimated the LTP effects on AMPAR subunit composition and distribution. The density and types of dendritic spines were quantified by using the Golgi staining method. MPH completely restored the behavioral impairments of PNE mice. Reduced LTP and AMPA-receptor-mediated EPSCs were also restored. EPSC amplitudes were tightly correlated with numbers of GluA1/GluA1 AMPA receptors at the cell surface. Finally, we found a lower density of dendritic spines in hippocampal pyramidal neurons in PNE mice, with a higher fraction of thin-type immature spines and a lower fraction of mushroom mature spines; the latter effect was also reversed by MPH.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Metilfenidato , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Metilfenidato/farmacologia , Camundongos , Plasticidade Neuronal , Nicotina/metabolismo , Nicotina/farmacologia , Gravidez , Receptores de AMPA/metabolismo
15.
J Cell Biol ; 221(8)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35819332

RESUMO

IRSp53 (aka BAIAP2) is a scaffold protein that couples membranes with the cytoskeleton in actin-filled protrusions such as filopodia and lamellipodia. The protein is abundantly expressed in excitatory synapses and is essential for synapse development and synaptic plasticity, although with poorly understood mechanisms. Here we show that specific multivalent interactions between IRSp53 and its binding partners PSD-95 or Shank3 drive phase separation of the complexes in solution. IRSp53 can be enriched to the reconstituted excitatory PSD (ePSD) condensates via bridging to the core and deeper layers of ePSD. Overexpression of a mutant defective in the IRSp53/PSD-95 interaction perturbs synaptic enrichment of IRSp53 in mouse cortical neurons. The reconstituted PSD condensates promote bundled actin filament formation both in solution and on membranes, via IRSp53-mediated actin binding and bundling. Overexpression of mutants that perturb IRSp53-actin interaction leads to defects in synaptic maturation of cortical neurons. Together, our studies provide potential mechanistic insights into the physiological roles of IRSp53 in synapse formation and function.


Assuntos
Actinas , Proteínas do Tecido Nervoso , Densidade Pós-Sináptica , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Animais , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Densidade Pós-Sináptica/metabolismo , Pseudópodes/genética , Pseudópodes/metabolismo , Sinapses/genética , Sinapses/metabolismo
16.
JCI Insight ; 7(14)2022 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-35866480

RESUMO

Synaptic dysfunction is a manifestation of several neurobehavioral and neurological disorders. A major therapeutic challenge lies in uncovering the upstream regulatory factors controlling synaptic processes. Plant homeodomain (PHD) finger proteins are epigenetic readers whose dysfunctions are implicated in neurological disorders. However, the molecular mechanisms linking PHD protein deficits to disease remain unclear. Here, we generated a PHD finger protein 21B-depleted (Phf21b-depleted) mutant CRISPR mouse model (hereafter called Phf21bΔ4/Δ4) to examine Phf21b's roles in the brain. Phf21bΔ4/Δ4 animals exhibited impaired social memory. In addition, reduced expression of synaptic proteins and impaired long-term potentiation were observed in the Phf21bΔ4/Δ4 hippocampi. Transcriptome profiling revealed differential expression of genes involved in synaptic plasticity processes. Furthermore, we characterized a potentially novel interaction of PHF21B with histone H3 trimethylated lysine 36 (H3K36me3), a histone modification associated with transcriptional activation, and the transcriptional factor CREB. These results establish PHF21B as an important upstream regulator of synaptic plasticity-related genes and a candidate therapeutic target for neurobehavioral dysfunction in mice, with potential applications in human neurological and psychiatric disorders.


Assuntos
Proteínas de Homeodomínio , Doenças do Sistema Nervoso , Plasticidade Neuronal , Animais , Epigênese Genética , Regulação da Expressão Gênica , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Camundongos , Plasticidade Neuronal/genética
17.
Sci Rep ; 12(1): 12834, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896679

RESUMO

Tight regulation of immediate early gene (IEG) expression is important for synaptic plasticity, learning, and memory. Recent work has suggested that DNA double strand breaks (DSBs) may have an adaptive role in post-mitotic cells to induce IEG expression. Physiological activity in cultured neurons as well as behavioral training leads to increased DSBs and subsequent IEG expression. Additionally, infusion of etoposide-a common cancer treatment that induces DSBs-impairs trace fear memory. Here, we assessed the effects of hippocampal infusion of 60 ng of etoposide on IEG expression, learning, and memory in 3-4 month-old C57Bl/6J mice. Etoposide altered expression of the immediate early genes cFos and Arc in the hippocampus and impaired hippocampus-dependent contextual fear memory. These data add to the growing evidence that DSBs play an important role in IEG expression, learning, and memory, opening avenues for developing novel treatment strategies for memory-related disorders.


Assuntos
Genes Precoces , Hipocampo , Animais , Etoposídeo/farmacologia , Medo/fisiologia , Hipocampo/metabolismo , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal
18.
Int J Mol Sci ; 23(14)2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35887155

RESUMO

Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that exhibit enormous diversity in their expression patterns, sequence homology, pharmacology, biophysical properties and signaling pathways in the brain. In general, mGluRs modulate different traits of neuronal physiology, including excitability and plasticity processes. Particularly, group I mGluRs located at the pre- or postsynaptic compartments are involved in spike timing-dependent plasticity (STDP) at hippocampal and neocortical synapses. Their roles of participating in the underlying mechanisms for detection of activity coincidence in STDP induction are debated, and diverse findings support models involving mGluRs in STDP forms in which NMDARs do not operate as classical postsynaptic coincidence detectors. Here, we briefly review the involvement of group I mGluRs in STDP and their possible role as coincidence detectors.


Assuntos
Receptores de Glutamato Metabotrópico , Sinapses , Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo
19.
Cell Rep ; 40(3): 111101, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858575

RESUMO

Synapse loss and memory decline are the primary features of neurodegenerative dementia. However, the molecular underpinnings that drive memory loss remain largely unknown. Here, we report that FAM69C is a kinase critically involved in neurodegenerative dementia. Biochemical analyses uncover that FAM69C is a serine/threonine kinase. We generate the Fam69c knockout mice and show by single-cell RNA sequencing that FAM69C deficiency drives cell-type-specific transcriptional changes relevant to synapse dysfunction. Electrophysiological, morphological, and behavioral experiments demonstrate impairments in synaptic plasticity, dendritic spine density, and memory in Fam69c knockout mice, as well as stress-induced neuronal death. Phosphoproteomic characterizations reveal that FAM69C substrates are involved in synaptic structure and function. Finally, reduced levels of FAM69C are found in postmortem brains of Alzheimer's disease patients. Our study demonstrates that FAM69C is a protective regulator of memory and suggests FAM69C as a potential therapeutic target for memory loss in neurodegenerative dementia.


Assuntos
Doença de Alzheimer , Sinapses , Doença de Alzheimer/genética , Animais , Transtornos da Memória/genética , Camundongos , Camundongos Knockout , Plasticidade Neuronal/fisiologia
20.
PLoS One ; 17(7): e0271311, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35820111

RESUMO

While previous research using transcranial magnetic stimulation (TMS) suggest that cerebellum (CB) influences the neuroplastic response of primary motor cortex (M1), the role of different indirect (I) wave inputs in M1 mediating this interaction remains unclear. The aim of this study was therefore to assess how CB influences neuroplasticity of early and late I-wave circuits. 22 young adults (22 ± 2.7 years) participated in 3 sessions in which I-wave periodicity repetitive transcranial magnetic stimulation (iTMS) was applied over M1 during concurrent application of cathodal transcranial direct current stimulation over CB (tDCSCB). In each session, iTMS either targeted early I-waves (1.5 ms interval; iTMS1.5), late I-waves (4.5 ms interval; iTMS4.5), or had no effect (variable interval; iTMSSham). Changes due to the intervention were examined with motor evoked potential (MEP) amplitude using TMS protocols measuring corticospinal excitability (MEP1mV) and the strength of CB-M1 connections (CBI). In addition, we indexed I-wave activity using short-interval intracortical facilitation (SICF) and low-intensity single-pulse TMS applied with posterior-anterior (MEPPA) and anterior-posterior (MEPAP) current directions. Following both active iTMS sessions, there was no change in MEP1mV, CBI or SICF (all P > 0.05), suggesting that tDCSCB broadly disrupted the excitatory response that is normally seen following iTMS. However, although MEPAP also failed to facilitate after the intervention (P > 0.05), MEPPA potentiated following both active iTMS sessions (both P < 0.05). This differential response between current directions could indicate a selective effect of CB on AP-sensitive circuits.


Assuntos
Córtex Motor , Estimulação Transcraniana por Corrente Contínua , Cerebelo , Potencial Evocado Motor/fisiologia , Humanos , Córtex Motor/fisiologia , Plasticidade Neuronal , Adulto Jovem
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