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1.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445628

RESUMO

We investigated the alterations of hippocampal and reticulo-thalamic (RT) GABAergic parvalbumin (PV) interneurons and their synaptic re-organizations underlying the prodromal local sleep disorders in the distinct rat models of Parkinson's disease (PD). We demonstrated for the first time that REM sleep is a predisposing state for the high-voltage sleep spindles (HVS) induction in all experimental models of PD, particularly during hippocampal REM sleep in the hemiparkinsonian models. There were the opposite underlying alterations of the hippocampal and RT GABAergic PV+ interneurons along with the distinct MAP2 and PSD-95 expressions. Whereas the PD cholinopathy enhanced the number of PV+ interneurons and suppressed the MAP2/PSD-95 expression, the hemiparkinsonism with PD cholinopathy reduced the number of PV+ interneurons and enhanced the MAP2/PSD-95 expression in the hippocampus. Whereas the PD cholinopathy did not alter PV+ interneurons but partially enhanced MAP2 and suppressed PSD-95 expression remotely in the RT, the hemiparkinsonism with PD cholinopathy reduced the PV+ interneurons, enhanced MAP2, and did not change PSD-95 expression remotely in the RT. Our study demonstrates for the first time an important regulatory role of the hippocampal and RT GABAergic PV+ interneurons and the synaptic protein dynamic alterations in the distinct rat models of PD neuropathology.


Assuntos
Modelos Animais de Doenças , Hipocampo/patologia , Interneurônios/patologia , Doença de Parkinson/complicações , Parvalbuminas/metabolismo , Transtornos do Sono-Vigília/patologia , Sinapses/patologia , Animais , Proteína 4 Homóloga a Disks-Large/genética , Proteína 4 Homóloga a Disks-Large/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropatologia , Ratos , Ratos Wistar , Formação Reticular/metabolismo , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/metabolismo , Sinapses/metabolismo , Tálamo/metabolismo , Ácido gama-Aminobutírico/metabolismo
2.
Nat Commun ; 12(1): 4767, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362912

RESUMO

Axons in the cerebral cortex show a broad range of myelin coverage. Oligodendrocytes establish this pattern by selecting a cohort of axons for myelination; however, the distribution of myelin on distinct neurons and extent of internode replacement after demyelination remain to be defined. Here we show that myelination patterns of seven distinct neuron subtypes in somatosensory cortex are influenced by both axon diameter and neuronal identity. Preference for myelination of parvalbumin interneurons was preserved between cortical areas with varying myelin density, suggesting that regional differences in myelin abundance arises through local control of oligodendrogenesis. By imaging loss and regeneration of myelin sheaths in vivo we show that myelin distribution on individual axons was altered but overall myelin content on distinct neuron subtypes was restored. Our findings suggest that local changes in myelination are tolerated, allowing regenerated oligodendrocytes to restore myelin content on distinct neurons through opportunistic selection of axons.


Assuntos
Encéfalo/fisiologia , Córtex Cerebral/fisiologia , Bainha de Mielina/fisiologia , Neurônios/fisiologia , Regeneração/fisiologia , Animais , Axônios/fisiologia , Feminino , Interneurônios/fisiologia , Masculino , Camundongos , Oligodendroglia , Organogênese/fisiologia , Parvalbuminas , Córtex Somatossensorial
3.
Biomolecules ; 11(8)2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34439824

RESUMO

Strontium salts are used for treatment of osteoporosis and bone cancer, but their impact on calcium-mediated physiological processes remains obscure. To explore Sr2+ interference with Ca2+ binding to proteins of the EF-hand family, we studied Sr2+/Ca2+ interaction with a canonical EF-hand protein, α-parvalbumin (α-PA). Evaluation of the equilibrium metal association constants for the active Ca2+ binding sites of recombinant human α-PA ('CD' and 'EF' sites) from fluorimetric titration experiments and isothermal titration calorimetry data gave 4 × 109 M-1 and 4 × 109 M-1 for Ca2+, and 2 × 107 M-1 and 2 × 106 M-1 for Sr2+. Inactivation of the EF site by homologous substitution of the Ca2+-coordinating Glu in position 12 of the EF-loop by Gln decreased Ca2+/Sr2+ affinity of the protein by an order of magnitude, whereas the analogous inactivation of the CD site induced much deeper suppression of the Ca2+/Sr2+ affinity. These results suggest that Sr2+ and Ca2+ bind to CD/EF sites of α-PA and the Ca2+/Sr2+ binding are sequential processes with the CD site being occupied first. Spectrofluorimetric Sr2+ titration of the Ca2+-loaded α-PA revealed presence of secondary Sr2+ binding site(s) with an apparent equilibrium association constant of 4 × 105 M-1. Fourier-transform infrared spectroscopy data evidence that Ca2+/Sr2+-loaded forms of α-PA exhibit similar states of their COO- groups. Near-UV circular dichroism (CD) data show that Ca2+/Sr2+ binding to α-PA induce similar changes in symmetry of microenvironment of its Phe residues. Far-UV CD experiments reveal that Ca2+/Sr2+ binding are accompanied by nearly identical changes in secondary structure of α-PA. Meanwhile, scanning calorimetry measurements show markedly lower Sr2+-induced increase in stability of tertiary structure of α-PA, compared to the Ca2+-induced effect. Theoretical modeling using Density Functional Theory computations with Polarizable Continuum Model calculations confirms that Ca2+-binding sites of α-PA are well protected against exchange of Ca2+ for Sr2+ regardless of coordination number of Sr2+, solvent exposure or rigidity of sites. The latter appears to be a key determinant of the Ca2+/Sr2+ selectivity. Overall, despite lowered affinity of α-PA to Sr2+, the latter competes with Ca2+ for the same EF-hands and induces similar structural rearrangements. The presence of a secondary Sr2+ binding site(s) could be a factor contributing to Sr2+ impact on the functional activity of proteins.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cálcio/metabolismo , Parvalbuminas/metabolismo , Estrôncio/metabolismo , Sítios de Ligação , Proteínas de Ligação ao Cálcio/química , Proteínas de Ligação ao Cálcio/genética , Cátions Bivalentes , Clonagem Molecular , Teoria da Densidade Funcional , Motivos EF Hand , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Cinética , Parvalbuminas/química , Parvalbuminas/genética , Ligação Proteica , Estabilidade Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Soluções
4.
Nat Commun ; 12(1): 5116, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433814

RESUMO

NMDA receptor (NMDAR) and GABA neuronal dysfunctions are observed in animal models of autism spectrum disorders, but how these dysfunctions impair social cognition and behavior remains unclear. We report here that NMDARs in cortical parvalbumin (Pv)-positive interneurons cooperate with gap junctions to promote high-frequency (>80 Hz) Pv neuronal burst firing and social cognition. Shank2-/- mice, displaying improved sociability upon NMDAR activation, show impaired cortical social representation and inhibitory neuronal burst firing. Cortical Shank2-/- Pv neurons show decreased NMDAR activity, which suppresses the cooperation between NMDARs and gap junctions (GJs) for normal burst firing. Shank2-/- Pv neurons show compensatory increases in GJ activity that are not sufficient for social rescue. However, optogenetic boosting of Pv neuronal bursts, requiring GJs, rescues cortical social cognition in Shank2-/- mice, similar to the NMDAR-dependent social rescue. Therefore, NMDARs and gap junctions cooperate to promote cortical Pv neuronal bursts and social cognition.


Assuntos
Junções Comunicantes/metabolismo , Interneurônios/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Cognição Social , Sinapses/fisiologia , Animais , Junções Comunicantes/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Parvalbuminas/genética , Parvalbuminas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Comportamento Social , Sinapses/genética
5.
Nat Commun ; 12(1): 4610, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326331

RESUMO

Integration of multi-frequency sounds into a unified perceptual object is critical for recognizing syllables in speech. This "feature binding" relies on the precise synchrony of each component's onset timing, but little is known regarding its neural correlates. We find that multi-frequency sounds prevalent in vocalizations, specifically harmonics, preferentially activate the mouse secondary auditory cortex (A2), whose response deteriorates with shifts in component onset timings. The temporal window for harmonics integration in A2 was broadened by inactivation of somatostatin-expressing interneurons (SOM cells), but not parvalbumin-expressing interneurons (PV cells). Importantly, A2 has functionally connected subnetworks of neurons preferentially encoding harmonic over inharmonic sounds. These subnetworks are stable across days and exist prior to experimental harmonics exposure, suggesting their formation during development. Furthermore, A2 inactivation impairs performance in a discrimination task for coincident harmonics. Together, we propose A2 as a locus for multi-frequency integration, which may form the circuit basis for vocal processing.


Assuntos
Córtex Auditivo/fisiologia , Percepção Auditiva/fisiologia , Potenciais Evocados Auditivos/fisiologia , Interneurônios/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Parvalbuminas/metabolismo , Somatostatina/metabolismo , Som
6.
eNeuro ; 8(4)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083381

RESUMO

The orbitofrontal cortex (OFC) is a brain region involved in higher-order decision-making. Rodent studies show that cocaine self-administration (CSA) reduces OFC contribution to goal-directed behavior and behavioral strategies to avoid drug intake. This change in OFC function persists for many weeks after cocaine withdrawal, suggesting involvement in the process of addiction. The mechanisms underlying impaired OFC function by cocaine are not well-understood. However, studies implicate altered OFC serotonin (5-HT) function in disrupted cognitive processes during addiction and other psychiatric disorders. Thus, it is hypothesized that cocaine impairment of OFC function involves changes in 5-HT signaling, and previous work shows that 5-HT1A and 5-HT2A receptor-mediated effects on OFC pyramidal neurons (PyNs) are impaired weeks after cocaine withdrawal. However, 5-HT effects on other contributors to OFC circuit function have not been fully investigated, including the parvalbumin-containing, fast-spiking interneurons (OFCPV), whose function is essential to normal OFC-mediated behavior. Here, 5-HT function in naive rats and those withdrawn from CSA were evaluated using a novel rat transgenic line in which the rat parvalbumin promoter drives Cre-recombinase expression to permit identification of OFCPV cells by fluorescent reporter protein expression. We find that whereas CSA altered basal synaptic and membrane properties of the OFCPV neurons in a sex-dependent manner, the effects of 5-HT on these cells were unchanged by CSA. These data suggest that the behavioral effects of dysregulated OFC 5-HT function caused by cocaine experience are primarily mediated by changes in 5-HT signaling at PyNs, and not at OFCPV neurons.


Assuntos
Cocaína , Animais , Integrases , Neurônios , Parvalbuminas , Córtex Pré-Frontal , Ratos , Serotonina
7.
J Phys Chem B ; 125(24): 6390-6405, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34115511

RESUMO

Members of the parvalbumin (PV) family of calcium (Ca2+) binding proteins (CBPs) share a relatively high level of sequence similarity. However, their Ca2+ affinities and selectivities against competing ions like Mg2+ can widely vary. We conducted molecular dynamics simulations of several α-parvalbumin (αPV) constructs with micromolar to nanomolar Ca2+ affinities to identify structural and dynamic features that contribute to their binding of ions. Specifically, we examined a D94S/G98E construct with a lower Ca2+ affinity (≈-18 kcal/mol) relative to the wild type (WT) (≈-22 kcal/mol) and an S55D/E59D variant with enhanced affinity (≈-24 kcal/mol). Additionally, we also examined the binding of Mg2+ to these isoforms, which is much weaker than Ca2+. We used mean spherical approximation (MSA) theory to evaluate ion binding thermodynamics within the proteins' EF-hand domains to account for the impact of ions' finite sizes and the surrounding electrolyte composition. While the MSA scores differentiated Mg2+ from Ca2+, they did not indicate that Ca2+ binding affinities at the binding loop differed between the PV isoforms. Instead, molecular mechanics generalized Born surface area (MM/GBSA) approximation energies, which we used to quantify the thermodynamic cost of structural rearrangement of the proteins upon binding ions, indicated that S55D/E59D αPV favored Ca2+ binding by -20 kcal/mol relative to WT versus 30 kcal/mol for D94S/G98E αPV. Meanwhile, Mg2+ binding was favored for the S55D/E59D αPV and D94S/G98E αPV variants by -18.32 and -1.65 kcal/mol, respectively. These energies implicate significant contributions to ion binding beyond oxygen coordination at the binding loop, which stemmed from changes in α-helicity, ß-sheet character, and hydrogen bonding. Hence, Ca2+ affinity and selectivity against Mg2+ are emergent properties stemming from both local effects within the proteins' ion binding sites as well as non-local contributions elsewhere. Our findings broaden our understanding of the molecular bases governing αPV ion binding that are likely shared by members of the broad family of CBPs.


Assuntos
Cálcio , Parvalbuminas , Sítios de Ligação , Cálcio/metabolismo , Parvalbuminas/metabolismo , Ligação Proteica , Termodinâmica
8.
Neurosci Bull ; 37(9): 1325-1338, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34143365

RESUMO

A strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-NTM) mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze (EPM) and showed reduced social preference in a three-chamber social interaction test. Following EPM tests, c-Fos expression levels indicated that the nucleus accumbens (NAc) was associated with risk-avoidance behavior in DISC1-NTM mice. In addition, in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons (FS) in the NAc were significantly lower in DISC1-NTM mice than in wild-type (WT) mice. In addition, in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV) neurons in the NAc of DISC1-NTM mice than in WT controls. The impairment of risk avoidance in DISC1-NTM mice was rescued using optogenetic tools that activated NAcPV neurons. Finally, inhibition of the activity of NAcPV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-NTM mice during tests on the elevated zero maze. Taken together, our findings confirm an impairment in risk avoidance in DISC1-NTM mice and suggest that reduced excitability of NAcPV neurons is responsible.


Assuntos
Núcleo Accumbens , Parvalbuminas , Animais , Interneurônios/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Parvalbuminas/metabolismo
9.
Food Chem ; 364: 130308, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34157591

RESUMO

Fish is one of the eight major foods causing type-I food allergy, and the prevalence of its allergy is increasing in part due to changes in consumption habits. One of the main drivers for these changes has been the processing developments transforming the fish muscle into seafood products. Most fish allergic patients react to the Ca2+-binding protein ß-parvalbumin (ß-PV) abundant in muscle. Here we have analyzed the effect of processing in the content and allergenic properties of the ß-PV. We found that the transformation process decreases the ß-PV content (4.7 ± 0.3 mg/g muscle, 0.24 ± 0.03 mg/g surimi, ≤0.003 ± 0.001 mg/g in seafood products), reduces the specific-IgE binding and prevents allergy relevant properties such the protease resistance and amyloid aggregation. These results suggest seafood products as potentially tolerable foods for fish allergic patients, but milk and egg allergic patients should be aware of the presence relevant additives.


Assuntos
Hipersensibilidade Alimentar , Parvalbuminas , Alérgenos , Animais , Produtos Pesqueiros , Humanos , Músculos , Alimentos Marinhos
10.
Nat Commun ; 12(1): 3653, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135323

RESUMO

The Mechanistic Target Of Rapamycin Complex 1 (mTORC1) pathway controls several aspects of neuronal development. Mutations in regulators of mTORC1, such as Tsc1 and Tsc2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. The correct development of inhibitory interneurons is crucial for functional circuits. In particular, the axonal arborisation and synapse density of parvalbumin (PV)-positive GABAergic interneurons change in the postnatal brain. How and whether mTORC1 signaling affects PV cell development is unknown. Here, we show that Tsc1 haploinsufficiency causes a premature increase in terminal axonal branching and bouton density formed by mutant PV cells, followed by a loss of perisomatic innervation in adult mice. PV cell-restricted Tsc1 haploinsufficient and knockout mice show deficits in social behavior. Finally, we identify a sensitive period during the third postnatal week during which treatment with the mTOR inhibitor Rapamycin rescues deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. Our findings reveal a role of mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and support a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.


Assuntos
Interneurônios/patologia , Parvalbuminas/metabolismo , Comportamento Social , Proteína 1 do Complexo Esclerose Tuberosa/deficiência , Animais , Autofagia , Axônios/efeitos dos fármacos , Axônios/patologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Mutação , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/patologia , Fatores de Tempo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo
11.
Neuroscience ; 467: 73-80, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34048799

RESUMO

The episodes of brief unconsciousness in patients with childhood absence epilepsy are a result of corticothalamocortical circuitry dysfunction. This dysfunction may arise from multifactorial mechanisms in patients from different genetic backgrounds. In previous studies using the epileptic stargazer mutant mouse, which experience frequent absence seizures, we reported a deficit in AMPAR-mediated feed-forward inhibition of parvalbumin-containing (PV+) interneurons. Currently, in order to determine the downstream effects of this impairment on neurotransmitter expression, we performed HPLC of tissue lysates and post-embedding electron microscopy from the cortical and thalamic regions. We report region-specific alterations in GABA expression, but not of glutamate, and most prominently at PV+ synaptic terminals. These results suggest that impaired feed forward inhibition may occur via reduced activation of these interneurons and concomitant decreased GABAergic signaling. Further investigations into GABAergic control of corticothalamocortical network activity could be key in our understanding of absence seizure pathogenesis.


Assuntos
Epilepsia Tipo Ausência , Animais , Criança , Modelos Animais de Doenças , Humanos , Interneurônios , Camundongos , Neurotransmissores , Parvalbuminas
12.
Neuron ; 109(10): 1583-1584, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34015262

RESUMO

Wang et al. (2021) characterize the molecular, cellular, and circuit-level role of Oligophrenin-1 in prefrontal parvalbumin interneurons, demonstrating that loss of Ophn1 function in these neurons is a mechanism for increased susceptibility to stress in intellectual disability caused by OPHN1 mutations.


Assuntos
Deficiência Intelectual , Proteínas do Citoesqueleto/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Deficiência Intelectual/genética , Interneurônios/metabolismo , Proteínas Nucleares/metabolismo , Parvalbuminas , Córtex Pré-Frontal/metabolismo
13.
Biol Psychiatry ; 90(1): 47-57, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33892915

RESUMO

BACKGROUND: Visuospatial working memory (vsWM), which is commonly impaired in schizophrenia, involves information processing across the primary visual cortex, association visual cortex, posterior parietal cortex, and dorsolateral prefrontal cortex (DLPFC). Within these regions, vsWM requires inhibition from parvalbumin-expressing basket cells (PVBCs). Here, we analyzed indices of PVBC axon terminals across regions of the vsWM network in schizophrenia. METHODS: For 20 matched pairs of subjects with schizophrenia and unaffected comparison subjects, tissue sections from the primary visual cortex, association visual cortex, posterior parietal cortex, and DLPFC were immunolabeled for PV, the 65- and 67-kDa isoforms of glutamic acid decarboxylase (GAD65 and GAD67) that synthesize GABA (gamma-aminobutyric acid), and the vesicular GABA transporter. The density of PVBC terminals and of protein levels per terminal was quantified in layer 3 of each cortical region using fluorescence confocal microscopy. RESULTS: In comparison subjects, all measures, except for GAD65 levels, exhibited a caudal-to-rostral decline across the vsWM network. In subjects with schizophrenia, the density of detectable PVBC terminals was significantly lower in all regions except the DLPFC, whereas PVBC terminal levels of PV, GAD67, and GAD65 proteins were lower in all regions. A composite measure of inhibitory strength was lower in subjects with schizophrenia, although the magnitude of the diagnosis effect was greater in the primary visual, association visual, and posterior parietal cortices than in the DLPFC. CONCLUSIONS: In schizophrenia, alterations in PVBC terminals across the vsWM network suggest the presence of a shared substrate for cortical dysfunction during vsWM tasks. However, regional differences in the magnitude of the disease effect on an index of PVBC inhibitory strength suggest region-specific alterations in information processing during vsWM tasks.


Assuntos
Parvalbuminas , Esquizofrenia , Glutamato Descarboxilase/metabolismo , Humanos , Memória de Curto Prazo , Parvalbuminas/metabolismo , Córtex Pré-Frontal/metabolismo
14.
Neuron ; 109(10): 1636-1656.e8, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-33831348

RESUMO

Ample evidence indicates that individuals with intellectual disability (ID) are at increased risk of developing stress-related behavioral problems and mood disorders, yet a mechanistic explanation for such a link remains largely elusive. Here, we focused on characterizing the syndromic ID gene oligophrenin-1 (OPHN1). We find that Ophn1 deficiency in mice markedly enhances helpless/depressive-like behavior in the face of repeated/uncontrollable stress. Strikingly, Ophn1 deletion exclusively in parvalbumin (PV) interneurons in the prelimbic medial prefrontal cortex (PL-mPFC) is sufficient to induce helplessness. This behavioral phenotype is mediated by a diminished excitatory drive onto Ophn1-deficient PL-mPFC PV interneurons, leading to hyperactivity in this region. Importantly, suppressing neuronal activity or RhoA/Rho-kinase signaling in the PL-mPFC reverses helpless behavior. Our results identify OPHN1 as a critical regulator of adaptive behavioral responses to stress and shed light onto the mechanistic links among OPHN1 genetic deficits, mPFC circuit dysfunction, and abnormalities in stress-related behaviors.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Interneurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/metabolismo , Animais , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Proteínas Ativadoras de GTPase/deficiência , Proteínas Ativadoras de GTPase/genética , Células HEK293 , Desamparo Aprendido , Humanos , Interneurônios/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Parvalbuminas/genética , Parvalbuminas/metabolismo , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Estresse Psicológico/fisiopatologia , Transmissão Sináptica
15.
Elife ; 102021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33900199

RESUMO

Understanding the connectivity observed in the brain and how it emerges from local plasticity rules is a grand challenge in modern neuroscience. In the primary visual cortex (V1) of mice, synapses between excitatory pyramidal neurons and inhibitory parvalbumin-expressing (PV) interneurons tend to be stronger for neurons that respond to similar stimulus features, although these neurons are not topographically arranged according to their stimulus preference. The presence of such excitatory-inhibitory (E/I) neuronal assemblies indicates a stimulus-specific form of feedback inhibition. Here, we show that activity-dependent synaptic plasticity on input and output synapses of PV interneurons generates a circuit structure that is consistent with mouse V1. Computational modeling reveals that both forms of plasticity must act in synergy to form the observed E/I assemblies. Once established, these assemblies produce a stimulus-specific competition between pyramidal neurons. Our model suggests that activity-dependent plasticity can refine inhibitory circuits to actively shape cortical computations.


Assuntos
Interneurônios/fisiologia , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Células Piramidais/fisiologia , Córtex Visual/fisiologia , Animais , Camundongos , Parvalbuminas/metabolismo , Sinapses/fisiologia
16.
Transl Psychiatry ; 11(1): 222, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859158

RESUMO

Running exercise was shown to have a positive effect on depressive-like symptoms in many studies, but the underlying mechanism of running exercise in the treatment of depression has not been determined. Parvalbumin-positive interneurons (PV+ interneurons), a main subtype of GABA neurons, were shown to be decreased in the brain during the depression. PGC-1α, a molecule that is strongly related to running exercise, was shown to regulate PV+ interneurons. In the present study, we found that running exercise increased the expression of PGC-1α in the hippocampus of depressed mice. Adult male mice with PGC-1α gene silencing in the hippocampus ran on a treadmill for 4 weeks. Then, depression-like behavior was evaluated by the behavioral tests, and the PV+ interneurons in the hippocampus were investigated. We found that running exercise could not improve depressive-like symptoms or increase the gene expression of PV because of the lack of PGC-1α in the hippocampus. Moreover, a lack of PGC-1α in the hippocampus decreased the number and activity of PV+ interneurons in the CA3 subfield of the hippocampus, and running exercise could not reverse the pathological changes because of the lack of PGC-1α. The present study demonstrated that running exercise regulates PV+ interneurons through PGC-1α in the hippocampus of mice to reverse depressive-like behaviors. These data indicated that hippocampal PGC-1α-mediated positive effects on parvalbumin interneurons are required for the antidepressant actions of running exercise. Our results will help elucidate the antidepressant mechanism of running exercise and identify new targets for antidepressant treatment.


Assuntos
Parvalbuminas , Corrida , Animais , Antidepressivos , Hipocampo/metabolismo , Interneurônios/metabolismo , Masculino , Camundongos , Parvalbuminas/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo
17.
PLoS One ; 16(4): e0250262, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33878144

RESUMO

Valproic acid (VPA) treatment is associated with autism spectrum disorder in humans, and ferrets can be used as a model to test this; so far, it is not known whether ferrets react to developmental VPA exposure with gyrencephalic abnormalities. The current study characterized gyrification abnormalities in ferrets following VPA exposure during neonatal periods, corresponding to the late stage of cortical neurogenesis as well as the early stage of sulcogyrogenesis. Ferret pups received intraperitoneal VPA injections (200 µg/g of body weight) on postnatal days (PD) 6 and 7. BrdU was administered simultaneously at the last VPA injection. Ex vivo MRI-based morphometry demonstrated significantly lower gyrification index (GI) throughout the cortex in VPA-treated ferrets (1.265 ± 0.027) than in control ferrets (1.327 ± 0.018) on PD 20, when primary sulcogyrogenesis is complete. VPA-treated ferrets showed significantly smaller sulcal-GIs in the rostral suprasylvian sulcus and splenial sulcus but a larger lateral sulcus surface area than control ferrets. The floor cortex of the inner stratum of both the rostral suprasylvian and splenial sulci and the outer stratum of the lateral sulcus showed a relatively prominent expansion. Parvalbumin-positive neuron density was significantly greater in the expanded cortical strata of sulcal floors in VPA-treated ferrets, regardless of the BrdU-labeled status. Thus, VPA exposure during the late stage of cortical neurogenesis may alter gyrification, primarily in the frontal and parietotemporal cortical divisions. Altered gyrification may thicken the outer or inner stratum of the cerebral cortex by increasing parvalbumin-positive neuron density.


Assuntos
Anticonvulsivantes/efeitos adversos , Lobo Frontal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Lobo Parietal/efeitos dos fármacos , Lobo Temporal/efeitos dos fármacos , Ácido Valproico/efeitos adversos , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Mapeamento Encefálico , Contagem de Células , Furões , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Expressão Gênica , Humanos , Imuno-Histoquímica , Injeções Intraperitoneais , Imageamento por Ressonância Magnética , Masculino , Morfogênese/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Neuroimagem , Neurônios/metabolismo , Neurônios/patologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/patologia , Parvalbuminas/genética , Parvalbuminas/metabolismo , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia
18.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33806936

RESUMO

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.


Assuntos
Comportamento Animal , Imunomodulação , Interneurônios/metabolismo , Lipopolissacarídeos/imunologia , Parvalbuminas/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Feminino , Imuno-Histoquímica , Masculino , Exposição Materna , Microglia/imunologia , Microglia/metabolismo , Gravidez , Ratos , Fatores Sexuais , Comportamento Social
19.
Sheng Li Xue Bao ; 73(2): 295-305, 2021 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-33903891

RESUMO

Cortical GABAergic inhibitory neurons are composed of three major classes, each expressing parvalbumin (PV), somatostatin (SOM) and 5-hydroxytryptamine receptor 3A (Htr3a), respectively. Htr3a+ inhibitory neurons are mainly derived from the caudal ganglionic eminence (CGE). This highly heterogeneous group of inhibitory neurons are comprised of many different subtypes with distinct molecular signatures, morphological and electrophysiological properties and connectivity patterns. In this review, we summarized recent research progress regarding cortical Htr3a+ inhibitory neurons, focusing on their molecular, morphological and electrophysiological diversity, and introduced some genetic mouse tools that were used to study Htr3a+ inhibitory neurons.


Assuntos
Interneurônios , Serotonina , Animais , Interneurônios/metabolismo , Camundongos , Neurônios/metabolismo , Parvalbuminas/genética , Parvalbuminas/metabolismo , Receptores 5-HT3 de Serotonina/genética , Somatostatina/metabolismo
20.
Neurosci Res ; 167: 3-10, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33872635

RESUMO

Experience-dependent plasticity within visual cortex is controlled by postnatal maturation of inhibitory circuits, which are both morphologically diverse and precisely connected. Gene-targeted disruption of the voltage-dependent potassium channel Kv3.1 broadens action potentials and reduces net inhibitory function of parvalbumin (PV)-positive GABA subtypes within the neocortex. In mice lacking Kv3.1, the rate of input loss from an eye deprived of vision was slowed two-fold, despite otherwise normal critical period timecourse and receptive field properties. Rapid ocular dominance plasticity was restored by local or systemic enhancement of GABAergic transmission with acute benzodiazepine infusion. Diazepam instead exacerbated a global suppression of slow-wave oscillations during sleep described previously in these mutant mice, which therefore did not account for the rescued plasticity. Rapid ocular dominance shifts closely reflected Kv3.1 gene dosage that prevented prolonged spike discharge of their target pyramidal cells in vivo or the spike amplitude decrement of fast-spiking cells during bouts of high-frequency firing in vitro. Late postnatal expression of this unique channel in fast-spiking interneurons thus subtly regulates the speed of critical period plasticity with implications for mental illnesses.


Assuntos
Neocórtex , Canais de Potássio Shaw , Animais , Período Crítico Psicológico , Interneurônios/metabolismo , Camundongos , Neocórtex/metabolismo , Plasticidade Neuronal , Parvalbuminas/metabolismo , Canais de Potássio Shaw/genética , Canais de Potássio Shaw/metabolismo
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