RESUMO
p11, through unknown mechanisms, is required for behavioral and cellular responses to selective serotonin reuptake inhibitors (SSRIs). We show that SMARCA3, a chromatin-remodeling factor, is a target for the p11/annexin A2 heterotetrameric complex. Determination of the crystal structure indicates that SMARCA3 peptide binds to a hydrophobic pocket in the heterotetramer. Formation of this complex increases the DNA-binding affinity of SMARCA3 and its localization to the nuclear matrix fraction. In the dentate gyrus, both p11 and SMARCA3 are highly enriched in hilar mossy cells and basket cells. The SSRI fluoxetine induces expression of p11 in both cell types and increases the amount of the ternary complex of p11/annexin A2/SMARCA3. SSRI-induced neurogenesis and behavioral responses are abolished by constitutive knockout of SMARCA3. Our studies indicate a central role for a chromatin-remodeling factor in the SSRI/p11 signaling pathway and suggest an approach to the development of improved antidepressant therapies. PAPERCLIP:
Assuntos
Anexina A2/metabolismo , Proteínas de Ligação a DNA/metabolismo , Giro Denteado/metabolismo , Proteínas S100/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Ligação a DNA/química , Feminino , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Fibras Musgosas Hipocampais/metabolismo , Alinhamento de Sequência , Transdução de Sinais , Fatores de Transcrição/química , Difração de Raios XRESUMO
Our understanding of current treatments for depression, and the development of more specific therapies, is limited by the complexity of the circuits controlling mood and the distributed actions of antidepressants. Although the therapeutic efficacy of serotonin-specific reuptake inhibitors (SSRIs) is correlated with increases in cortical activity, the cell types crucial for their action remain unknown. Here we employ bacTRAP translational profiling to show that layer 5 corticostriatal pyramidal cells expressing p11 (S100a10) are strongly and specifically responsive to chronic antidepressant treatment. This response requires p11 and includes the specific induction of Htr4 expression. Cortex-specific deletion of p11 abolishes behavioral responses to SSRIs, but does not lead to increased depression-like behaviors. Our data identify corticostriatal projection neurons as critical for the response to antidepressants, and suggest that the regulation of serotonergic tone in this single cell type plays a pivotal role in antidepressant therapy.
Assuntos
Antidepressivos/metabolismo , Depressão/tratamento farmacológico , Neurônios/citologia , Córtex Pré-Frontal/citologia , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Animais , Antidepressivos/farmacologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mutação , Córtex Pré-Frontal/metabolismo , Células Piramidais/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
Innate immunity is associated with Alzheimer's disease1, but the influence of immune activation on the production of amyloid-ß is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-ß. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-ß. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.
Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Imunidade Inata , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Idade de Início , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/imunologia , Envelhecimento/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/química , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/metabolismo , Domínio Catalítico , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Inflamação , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/metabolismo , Proteínas de Ligação a RNA/genética , Risco , Regulação para CimaRESUMO
Aberrant cleavage of amyloid precursor protein (APP) by γ-secretase is closely associated with Alzheimer's disease (AD). γ-secretase activating protein (GSAP) specifically promotes γ-secretasemediated cleavage of APP. However, the underlying mechanism remains enigmatic. Here, we demonstrate that the 16-kDa C-terminal fragment of GSAP (GSAP-16K) undergoes phase separation in vitro and forms puncta-like condensates in cells. GSAP-16K exerts dual modulation on γ-secretase cleavage; GSAP-16K in dilute phase increases APPC-terminal 99-residue fragment (C99) cleavage toward preferred production of ß-amyloid peptide 42 (Aß42), but GSAP-16K condensates reduce APP-C99 cleavage through substrate sequestration. Notably, the Aß42/Aß40 ratio is markedly elevated with increasing concentrations of GSAP-16K. GSAP-16K stably associates with APP-C99 through specific sequence elements. These findings mechanistically explain GSAP-mediated modulation of γ-secretase activity that may have ramifications on the development of potential therapeutics.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Humanos , Fragmentos de Peptídeos/metabolismoRESUMO
Forebrain dopamine-sensitive (dopaminoceptive) neurons play a key role in movement, action selection, motivation, and working memory. Their activity is altered in Parkinson's disease, addiction, schizophrenia, and other conditions, and drugs that stimulate or antagonize dopamine receptors have major therapeutic applications. Yet, similarities and differences between the various neuronal populations sensitive to dopamine have not been systematically explored. To characterize them, we compared translating mRNAs in the dorsal striatum and nucleus accumbens neurons expressing D1 or D2 dopamine receptor and prefrontal cortex neurons expressing D1 receptor. We identified genome-wide cortico-striatal, striatal D1/D2 and dorso/ventral differences in the translating mRNA and isoform landscapes, which characterize dopaminoceptive neuronal populations. Expression patterns and network analyses identified novel transcription factors with presumptive roles in these differences. Prostaglandin E2 (PGE2) was a candidate upstream regulator in the dorsal striatum. We pharmacologically explored this hypothesis and showed that misoprostol, a PGE2 receptor agonist, decreased the excitability of D2 striatal projection neurons in slices, and diminished their activity in vivo during novel environment exploration. We found that misoprostol also modulates mouse behavior including by facilitating reversal learning. Our study provides powerful resources for characterizing dopamine target neurons, new information about striatal gene expression patterns and regulation. It also reveals the unforeseen role of PGE2 in the striatum as a potential neuromodulator and an attractive therapeutic target.
Assuntos
Dinoprostona , Misoprostol , Animais , Corpo Estriado/metabolismo , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Éxons , Expressão Gênica , Camundongos , Misoprostol/metabolismo , Misoprostol/farmacologia , RNA Mensageiro/metabolismo , Receptores de Dopamina D1/metabolismoRESUMO
The cellular heterogeneity of the brain confounds efforts to elucidate the biological properties of distinct neuronal populations. Using bacterial artificial chromosome (BAC) transgenic mice that express EGFP-tagged ribosomal protein L10a in defined cell populations, we have developed a methodology for affinity purification of polysomal mRNAs from genetically defined cell populations in the brain. The utility of this approach is illustrated by the comparative analysis of four types of neurons, revealing hundreds of genes that distinguish these four cell populations. We find that even two morphologically indistinguishable, intermixed subclasses of medium spiny neurons display vastly different translational profiles and present examples of the physiological significance of such differences. This genetically targeted translating ribosome affinity purification (TRAP) methodology is a generalizable method useful for the identification of molecular changes in any genetically defined cell type in response to genetic alterations, disease, or pharmacological perturbations.
Assuntos
Encéfalo/metabolismo , Técnicas Genéticas , Biossíntese de Proteínas , Animais , Sistema Nervoso Central/metabolismo , Cromossomos Artificiais Bacterianos/metabolismo , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Proteínas de Fluorescência Verde/metabolismo , Imuno-Histoquímica/métodos , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Neurônios/metabolismo , Ribossomos/metabolismoRESUMO
Comparative analysis can provide important insights into complex biological systems. As demonstrated in the accompanying paper, translating ribosome affinity purification (TRAP) permits comprehensive studies of translated mRNAs in genetically defined cell populations after physiological perturbations. To establish the generality of this approach, we present translational profiles for 24 CNS cell populations and identify known cell-specific and enriched transcripts for each population. We report thousands of cell-specific mRNAs that were not detected in whole-tissue microarray studies and provide examples that demonstrate the benefits deriving from comparative analysis. To provide a foundation for further biological and in silico studies, we provide a resource of 16 transgenic mouse lines, their corresponding anatomic characterization, and translational profiles for cell types from a variety of central nervous system structures. This resource will enable a wide spectrum of molecular and mechanistic studies of both well-known and previously uncharacterized neural cell populations.
Assuntos
Encéfalo/metabolismo , Técnicas Genéticas , Biossíntese de Proteínas , Animais , Sistema Nervoso Central/metabolismo , Cromossomos Artificiais Bacterianos/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Imuno-Histoquímica/métodos , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribossomos/metabolismoRESUMO
Major depressive disorder (MDD) is a severe, common mood disorder. While reduced cerebrospinal fluid (CSF) flow adversely affects brain metabolism and fluid balance in the aging population and during development, only indirect evidence links aberrant CSF circulation with many diseases including neurological, neurodegenerative, and psychiatric disorders, such as anxiety and depression. Here we show a very high concentration of p11 as a key molecular determinant for depression in ependymal cells, which is significantly decreased in patients with MDD, and in two mouse models of depression induced by chronic stress, such as restraint and social isolation. The loss of p11 in ependymal cells causes disoriented ependymal planar cell polarity (PCP), reduced CSF flow, and depression-like and anxiety-like behaviors. p11 intrinsically controls PCP core genes, which mediates CSF flow. Viral expression of p11 in ependymal cells specifically rescues the pathophysiological and behavioral deficits caused by loss of p11. Taken together, our results identify a new role and a key molecular determinant for ependymal cell-driven CSF flow in mood disorders and suggest a novel strategy for development of treatments for stress-associated neurological, neurodegenerative, and psychiatric disorders.
Assuntos
Transtorno Depressivo Maior , Idoso , Animais , Transtornos de Ansiedade , Depressão/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , NeurogliaRESUMO
The delayed behavioral response to chronic antidepressants depends on dynamic changes in the hippocampus. It was suggested that the antidepressant protein p11 and the chromatin remodeling factor SMARCA3 mediate this delayed response by inducing transcriptional changes in hippocampal neurons. However, what target genes are regulated by the p11/SMARCA3 complex to mediate the behavioral response to antidepressants, and what cell type mediates these molecular changes remain unknown. Here we report that the p11/SMARCA3 complex represses Neurensin-2 transcription in hippocampal parvalbumin-expressing interneurons after chronic treatment with Selective Serotonin Reuptake Inhibitors (SSRI). The behavioral response to antidepressants requires upregulation of p11, accumulation of SMARCA3 in the cell nucleus, and a consequent repression of Neurensin-2 transcription in these interneurons. We elucidate a functional role for p11/SMARCA3/Neurensin-2 pathway in regulating AMPA-receptor signaling in parvalbumin-expressing interneurons, a function that is enhanced by chronic treatment with SSRIs. These results link SSRIs to dynamic glutamatergic changes and implicate p11/SMARCA3/Neurensin-2 pathway in the development of more specific and efficient therapeutic strategies for neuropsychiatric disorders.
Assuntos
Antidepressivos , Proteínas de Ligação a DNA/metabolismo , Interneurônios/efeitos dos fármacos , Parvalbuminas , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fatores de Transcrição/metabolismo , Animais , Antidepressivos/farmacologia , Hipocampo/metabolismo , Interneurônios/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Parvalbuminas/metabolismoRESUMO
Among the hallmarks of major depressive disorders (MDD) are molecular, functional, and morphological impairments in the hippocampus. Recent studies suggested a key role for hippocampal GABAergic interneurons both in depression and in the response to its treatments. These interneurons highly express the chromatin-remodeler SMARCA3 which mediates the response to chronic antidepressants in an unknown mechanism. Using cell-type-specific molecular and physiological approaches, we report that SMARCA3 mediates the glutamatergic signaling in interneurons by repressing the expression of the neuronal protein, Neurensin-2. This vesicular protein associates with endosomes and postsynaptic proteins and is highly and selectively expressed in subpopulations of GABAergic interneurons. Upregulation of Neurensin-2 in the hippocampus either by stress, viral overexpression, or by SMARCA3 deletion, results in depressive-like behaviors. In contrast, the deletion of Neurensin-2 confers resilience to stress and induces AMPA receptor localization to synapses. This pathway which bidirectionally affects emotional behavior could be involved in neuropsychiatric disorders, and suggests novel therapeutic approaches.
Assuntos
Transtorno Depressivo Maior , Hipocampo , Humanos , Interneurônios , Neurônios , SinapsesRESUMO
Amyloid-ß peptide (Aß) accumulation in the brain is a hallmark of Alzheimer's Disease. An important mechanism of Aß clearance in the brain is uptake and degradation by microglia. Presenilin 1 (PS1) is the catalytic subunit of γ-secretase, an enzyme complex responsible for the maturation of multiple substrates, such as Aß. Although PS1 has been extensively studied in neurons, the role of PS1 in microglia is incompletely understood. Here we report that microglia containing phospho-deficient mutant PS1 display a slower kinetic response to micro injury in the brain in vivo and the inability to degrade Aß oligomers due to a phagolysosome dysfunction. An Alzheimer's mouse model containing phospho-deficient PS1 show severe Aß accumulation in microglia as well as the postsynaptic protein PSD95. Our results demonstrate a novel mechanism by which PS1 modulates microglial function and contributes to Alzheimer's -associated phenotypes.
Assuntos
Doença de Alzheimer , Microglia , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Camundongos , Microglia/metabolismo , Fosforilação , Presenilina-1/genética , Presenilina-1/metabolismoRESUMO
Serotonin receptor 4 (5-HT4R) plays an important role in regulating mood, anxiety, and cognition, and drugs that activate this receptor have fast-acting antidepressant (AD)-like effects in preclinical models. However, 5-HT4R is widely expressed throughout the central nervous system (CNS) and periphery, making it difficult to pinpoint the cell types and circuits underlying its effects. Therefore, we generated a Cre-dependent 5-HT4R knockout mouse line to dissect the function of 5-HT4R in specific brain regions and cell types. We show that the loss of functional 5-HT4R specifically from excitatory neurons of hippocampus led to robust AD-like behavioral responses and an elevation in baseline anxiety. 5-HT4R was necessary to maintain the proper excitability of dentate gyrus (DG) granule cells and cell type-specific molecular profiling revealed a dysregulation of genes necessary for normal neural function and plasticity in cells lacking 5-HT4R. These adaptations were accompanied by an increase in the number of immature neurons in ventral, but not dorsal, dentate gyrus, indicating a broad impact of 5-HT4R loss on the local cellular environment. This study is the first to use conditional genetic targeting to demonstrate a direct role for hippocampal 5-HT4R signaling in modulating mood and anxiety. Our findings also underscore the need for cell type-based approaches to elucidate the complex action of neuromodulatory systems on distinct neural circuits.
Assuntos
Ansiedade , Hipocampo , Animais , Giro Denteado/metabolismo , Hipocampo/metabolismo , Camundongos , Neurônios/metabolismo , Receptores de Serotonina , Receptores 5-HT4 de Serotonina/genética , Receptores 5-HT4 de Serotonina/metabolismoRESUMO
The mechanism by which γ-secretase activating protein (GSAP) regulates γ-secretase activity has not yet been elucidated. Here, we show that knockout of GSAP in cultured cells directly reduces γ-secretase activity for Aß production, but not for Notch1 cleavage, suggesting that GSAP may induce a conformational change contributing to the specificity of γ-secretase. Furthermore, using an active-site-directed photoprobe with double cross-linking moieties, we demonstrate that GSAP modifies the orientation and/or distance of the PS1 N-terminal fragment and the PS1 C-terminal fragment, a region containing the active site of γ-secretase. This work offers insight into how GSAP regulates γ-secretase specificity.
Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Presenilina-1/química , Proteínas/metabolismo , Sistemas CRISPR-Cas , Domínio Catalítico , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Cinética , Fragmentos de Peptídeos/metabolismo , Proteínas/genética , Receptor Notch1RESUMO
Extensive preclinical research has been conducted in recent years to reveal the cell types, neuronal circuits and molecular and morphological changes implicated in the function of the dentate gyrus in depression. This was profoundly facilitated by the emergence of methods such as gene targeting, neuronal cell activity manipulation, including optogenetics and chemogenetics, and the development of novel RNA sequencing technology and powerful MRI imagers that were used in clinical studies. These advancements provided researchers with the precise skills needed to evaluate the changes in the dentate gyrus structure and cell function in rodent models as well as in brains of depressed and medicated patients. Here, we review these latest findings and discuss the existing gaps in our knowledge of the role of the dentate gyrus in depression and in mediating the response to antidepressant therapies.
Assuntos
Giro Denteado , Depressão , Encéfalo , Humanos , Neurônios , OptogenéticaRESUMO
The cognitive mechanisms underlying attention-deficit hyperactivity disorder (ADHD), a highly heritable disorder with an array of candidate genes and unclear genetic architecture, remain poorly understood. We previously demonstrated that mice overexpressing CK1δ (CK1δ OE) in the forebrain show hyperactivity and ADHD-like pharmacological responses to D-amphetamine. Here, we demonstrate that CK1δ OE mice exhibit impaired visual attention and a lack of D-amphetamine-induced place preference, indicating a disruption of the dopamine-dependent reward pathway. We also demonstrate the presence of abnormalities in the frontostriatal circuitry, differences in synaptic ultra-structures by electron microscopy, as well as electrophysiological perturbations of both glutamatergic and GABAergic transmission, as observed by altered frequency and amplitude of mEPSCs and mIPSCs. Furthermore, gene expression profiling by next-generation sequencing alone, or in combination with bacTRAP technology to study specifically Drd1a versus Drd2 medium spiny neurons, revealed that developmental CK1δ OE alters transcriptional homeostasis in the striatum, including specific alterations in Drd1a versus Drd2 neurons. These results led us to perform a fine molecular characterization of targeted gene networks and pathway analysis. Importantly, a large fraction of 92 genes identified by GWAS studies as associated with ADHD in humans are significantly altered in our mouse model. The multiple abnormalities described here might be responsible for synaptic alterations and lead to complex behavioral abnormalities. Collectively, CK1δ OE mice share characteristics typically associated with ADHD and should represent a valuable model to investigate the disease in vivo.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Caseína Quinase Idelta/genética , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Corpo Estriado , Dopamina , Camundongos , Neurônios , Receptores de Dopamina D2/genéticaRESUMO
The behavioral response to antidepressants is closely associated with physiological changes in the function of neurons in the hippocampal dentate gyrus (DG). Parvalbumin interneurons are a major class of GABAergic neurons, essential for DG function, and are involved in the pathophysiology of several neuropsychiatric disorders. However, little is known about the role(s) of these neurons in major depressive disorder or in mediating the delayed behavioral response to antidepressants. Here we show, in mice, that hippocampal parvalbumin interneurons express functionally silent serotonin 5A receptors, which translocate to the cell membrane and become active upon chronic, but not acute, treatment with a selective serotonin reuptake inhibitor (SSRI). Activation of these serotonergic receptors in these neurons initiates a signaling cascade through which Gi-protein reduces cAMP levels and attenuates protein kinase A and protein phosphatase 2A activities. This results in increased phosphorylation and inhibition of Kv3.1ß channels, and thereby reduces the firing of the parvalbumin neurons. Through the loss of this signaling pathway in these neurons, conditional deletion of the serotonin 5A receptor leads to the loss of the physiological and behavioral responses to chronic antidepressants.
Assuntos
Antidepressivos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Parvalbuminas/metabolismo , Receptores de Serotonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/patologia , Feminino , Hipocampo/citologia , Humanos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , CamundongosRESUMO
Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed drugs for mood disorders. While the mechanism of SSRI action is still unknown, SSRIs are thought to exert therapeutic effects by elevating extracellular serotonin levels in the brain, and remodel the structural and functional alterations dysregulated during depression. To determine their precise mode of action, we tested whether such neuroadaptive processes are modulated by regulation of specific gene expression programs. Here we identify a transcriptional program regulated by activator protein-1 (AP-1) complex, formed by c-Fos and c-Jun that is selectively activated prior to the onset of the chronic SSRI response. The AP-1 transcriptional program modulates the expression of key neuronal remodeling genes, including S100a10 (p11), linking neuronal plasticity to the antidepressant response. We find that AP-1 function is required for the antidepressant effect in vivo. Furthermore, we demonstrate how neurochemical pathways of BDNF and FGF2, through the MAPK, PI3K, and JNK cascades, regulate AP-1 function to mediate the beneficial effects of the antidepressant response. Here we put forth a sequential molecular network to track the antidepressant response and provide a new avenue that could be used to accelerate or potentiate antidepressant responses by triggering neuroplasticity.
Assuntos
Anexina A2/metabolismo , Antidepressivos/farmacologia , Proteínas S100/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fator de Transcrição AP-1/metabolismo , Animais , Anexina A2/genética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , Ratos , Proteínas S100/genética , Serotonina/metabolismoRESUMO
Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activity-regulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.
Assuntos
Transtorno Autístico/tratamento farmacológico , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Proteínas dos Microfilamentos/deficiência , Proteínas do Tecido Nervoso/deficiência , Animais , Transtorno Autístico/genética , Modelos Animais de Doenças , Feminino , Haploinsuficiência , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Masculino , Metilação/efeitos dos fármacos , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Quinazolinas/farmacologiaRESUMO
Depression is a leading cause of disability. Current pharmacological treatment of depression is insufficient, and development of improved treatments especially for treatment-resistant depression is desired. Understanding the neurobiology of antidepressant actions may lead to development of improved therapeutic approaches. Here, we demonstrate that dopamine D1 receptors in the dentate gyrus act as a pivotal mediator of antidepressant actions in mice. Chronic administration of a selective serotonin reuptake inhibitor (SSRI), fluoxetine, increases D1 receptor expression in mature granule cells in the dentate gyrus. The increased D1 receptor signaling, in turn, contributes to the actions of chronic fluoxetine treatment, such as suppression of acute stress-evoked serotonin release, stimulation of adult neurogenesis and behavioral improvement. Importantly, under severely stressed conditions, chronic administration of a D1 receptor agonist in conjunction with fluoxetine restores the efficacy of fluoxetine actions on D1 receptor expression and behavioral responses. Thus, our results suggest that stimulation of D1 receptors in the dentate gyrus is a potential adjunctive approach to improve therapeutic efficacy of SSRI antidepressants.
Assuntos
Antidepressivos/farmacologia , Giro Denteado/metabolismo , Fluoxetina/farmacologia , Receptores de Dopamina D1/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Most antidepressants, including selective serotonin reuptake inhibitors (SSRIs), initiate their drug actions by rapid elevation of serotonin, but they take several weeks to achieve therapeutic onset. This therapeutic delay suggests slow adaptive changes in multiple neuronal subtypes and their neural circuits over prolonged periods of drug treatment. Mossy cells are excitatory neurons in the dentate hilus that regulate dentate gyrus activity and function. Here we show that neuronal activity of hippocampal mossy cells is enhanced by chronic, but not acute, SSRI administration. Behavioral and neurogenic effects of chronic treatment with the SSRI, fluoxetine, are abolished by mossy cell-specific knockout of p11 or Smarca3 or by an inhibition of the p11/AnxA2/SMARCA3 heterohexamer, an SSRI-inducible protein complex. Furthermore, simple chemogenetic activation of mossy cells using Gq-DREADD is sufficient to elevate the proliferation and survival of the neural stem cells. Conversely, acute chemogenetic inhibition of mossy cells using Gi-DREADD impairs behavioral and neurogenic responses to chronic administration of SSRI. The present data establish that mossy cells play a crucial role in mediating the effects of chronic antidepressant medication. Our results indicate that compounds that target mossy cell activity would be attractive candidates for the development of new antidepressant medications.