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1.
Cell ; 151(4): 709-723, 2012 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-23141534

RESUMO

Mutations that cause intellectual disability (ID) and autism spectrum disorder (ASD) are commonly found in genes that encode for synaptic proteins. However, it remains unclear how mutations that disrupt synapse function impact intellectual ability. In the SYNGAP1 mouse model of ID/ASD, we found that dendritic spine synapses develop prematurely during the early postnatal period. Premature spine maturation dramatically enhanced excitability in the developing hippocampus, which corresponded with the emergence of behavioral abnormalities. Inducing SYNGAP1 mutations after critical developmental windows closed had minimal impact on spine synapse function, whereas repairing these pathogenic mutations in adulthood did not improve behavior and cognition. These data demonstrate that SynGAP protein acts as a critical developmental repressor of neural excitability that promotes the development of life-long cognitive abilities. We propose that the pace of dendritic spine synapse maturation in early life is a critical determinant of normal intellectual development.


Assuntos
Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Espinhas Dendríticas/metabolismo , Sinapses/metabolismo , Proteínas Ativadoras de ras GTPase/genética , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Haploinsuficiência , Hipocampo/embriologia , Hipocampo/metabolismo , Humanos , Masculino , Memória , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/metabolismo
2.
J Neurochem ; 134(3): 429-44, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25931194

RESUMO

Myh9 and Myh10, which encode two major isoforms of non-muscle myosin II expressed in the brain, have emerged as risk factors for developmental brain disorders. Myosin II motors regulate neuronal cytoskeletal dynamics leading to optimization of synaptic plasticity and memory formation. However, the role of these motor complexes in brain development remains poorly understood. Here, we disrupted the in vivo expression of Myh9 and/or Myh10 in developing hippocampal neurons to determine how these motors contribute to circuit maturation in this brain area important for cognition. We found that Myh10 ablation in early postnatal, but not mature, CA1 pyramidal neurons reduced excitatory synaptic function in the Schaffer collateral pathway, whereas more distal inputs to CA1 neurons were relatively unaffected. Myh10 ablation in young neurons also selectively impaired the elongation of oblique dendrites that receive Schaffer collateral inputs, whereas the structure of distal dendrites was normal. We observed normal spine density and spontaneous excitatory currents in these neurons, indicating that Myh10 KO impaired proximal pathway synaptic maturation through disruptions to dendritic development rather than post-synaptic strength or spine morphogenesis. To address possible redundancy and/or compensation by other Myosin II motors expressed in neurons, we performed similar experiments in Myh9 null neurons. In contrast to findings in Myh10 mutants, evoked synaptic function in young Myh9 KO hippocampal neurons was normal. Data obtained from double Myh9/Myh10 KO neurons largely resembled the MyH10 KO synaptic phenotype. These data indicate that Myosin IIB is a key molecular factor that guides input-specific circuit maturation in the developing hippocampus. Non-muscle myosin II is an actin binding protein with three isoforms in the brain (IIA, IIB and IIC) encoded by the myh9, myh10, and myh14 genes in mice, respectively. We have studied the structure and the function of hippocampal CA1 neurons missing NMIIB and/or NMIIA proteins at different times during development. We have discovered that NMIIB is the major isoform regulating Schaffer collateral inputs, and that this regulation is restricted to early postnatal development.


Assuntos
Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Vias Neurais/crescimento & desenvolvimento , Neurogênese/fisiologia , Miosina não Muscular Tipo IIB/metabolismo , Animais , Western Blotting , Feminino , Masculino , Camundongos , Camundongos Knockout , Vias Neurais/metabolismo , Neurônios/metabolismo , Técnicas de Patch-Clamp
3.
Int J Neuropsychopharmacol ; 16(7): 1623-34, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23442571

RESUMO

Cpe(fat/fat) mice have a point mutation in carboxypeptidase E (Cpe), an exopeptidase that removes C-terminal basic amino acids from intermediates to produce bioactive peptides. The mutation renders the enzyme inactive and unstable. The absence of Cpe activity in these mutants leads to abnormal processing of many peptides, with elevated levels of intermediates and greatly reduced levels of the mature peptides. Cpe(fat/fat) mice develop obesity, diabetes and infertility in adulthood. We examined whether anxiety- and/or depressive-like behaviours are also present. Anxiety-like responses are not evident in young Cpe(fat/fat) mice (∼60 d), but appear in older animals (>90 d). These behaviours are reversed by acute treatment with diazepam or fluoxetine. In contrast, increased immobilities in forced swim and tail suspension are evident in all age groups examined. These behaviours are reversed by acute administration of reboxetine. In comparison acute treatments with fluoxetine or bupropion are ineffective; however, immobility times are normalized with 2 wk treatment. These data demonstrate that Cpe(fat/fat) mice display depressive-like responses aged ∼60 d, whereas anxiety-like behaviours emerge ∼1 month later. In tail suspension, the reboxetine findings show that noradrenergic actions of antidepressants are intact in Cpe(fat/fat) mice. The ability of acute fluoxetine treatment to rescue anxiety-like while leaving depressive-like responses unaffected suggests that serotonin mechanisms underlying these behaviours are different. Since depressive-like responses in the Cpe(fat/fat) mice are rescued by 2 wk, but not acute, treatment with fluoxetine or bupropion, these mice may serve as a useful model that resembles human depression.


Assuntos
Ansiedade/etiologia , Carboxipeptidase H/genética , Depressão/etiologia , Obesidade/complicações , Fatores Etários , Análise de Variância , Animais , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/genética , Depressão/tratamento farmacológico , Depressão/genética , Diazepam/uso terapêutico , Comportamento Exploratório/efeitos dos fármacos , Elevação dos Membros Posteriores/métodos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Morfolinas/uso terapêutico , Atividade Motora/efeitos dos fármacos , Obesidade/genética , Mutação Puntual/genética , Reboxetina , Natação/psicologia
4.
Elife ; 112022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35394425

RESUMO

Loss-of-function variants in SYNGAP1 cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP1 splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-α1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of α1/2 expression improved learning and increased seizure latency. Mice expressing α1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with α1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP-αexpression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.


Assuntos
Convulsões , Proteínas Ativadoras de ras GTPase , Animais , Cognição , Camundongos , Mutação , Isoformas de Proteínas/genética , Convulsões/genética , Sinapses/fisiologia , Proteínas Ativadoras de ras GTPase/genética , Proteínas Ativadoras de ras GTPase/metabolismo
5.
Bipolar Disord ; 13(3): 238-49, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21676127

RESUMO

OBJECTIVE: Altered muscarinic acetylcholine receptor levels and receptor-coupled signaling processes have been reported in mood disorders. M(1) , one of five muscarinic receptor subtypes, couples to the phospholipase C/protein kinase C and extracellular signal-regulated kinase (ERK) pathways. Mood stabilizers regulate these pathways. MicroRNAs (miRNAs) are small noncoding RNAs that suppress translation in a sequence-selective manner. Lithium downregulates several miRNAs, including let-7b and let-7c. One predicted target of let-7b and let-7c is the M(1) receptor. We hypothesized that miRNAs regulate M(1) receptor translation, and that disrupted M(1) expression leads to aberrant behaviors and disrupted downstream signaling pathways that are rescued by lithium treatment. METHODS: The effects of miRNAs and chronic treatment with mood stabilizers on M(1) levels were tested in primary cultures and in rat frontal cortex. Effects of M(1) ablation and chronic treatment with mood stabilizers on several signaling cascades and M(1) -modulated behaviors were examined in wild-type and M(1) knockout mice. RESULTS: Let-7b, but not let-7c, negatively regulated M(1) levels. Chronic treatment with lithium, but not valproate, increased M(1) levels in the rat cortex. M(1) knockout mice exhibit ERK pathway deficits and behavioral hyperactivity; chronic treatment with lithium attenuated these deficits and hyperactivity. CONCLUSIONS: Lithium treatment can affect M(1) receptor function through intracellular signaling enhancement and, in situations without M(1) ablation, concomitant receptor upregulation via mechanisms involving miRNAs. Muscarinic dysfunction may contribute to mood disorders, while M(1) receptors and the downstream ERK pathway may serve as potential therapeutic targets for alleviating manic symptoms such as psychomotor hyperactivity.


Assuntos
Antimaníacos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Lítio/farmacologia , Receptor Muscarínico M1/metabolismo , Anfetamina , Análise de Variância , Animais , Células Cultivadas , Córtex Cerebral/citologia , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Proteína GAP-43/metabolismo , Regulação da Expressão Gênica/genética , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Relações Interpessoais , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/farmacologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Substrato Quinase C Rico em Alanina Miristoilada , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Endogâmicos WKY , Receptor Muscarínico M1/deficiência , Natação/psicologia
6.
J Neurosci ; 28(1): 68-79, 2008 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-18171924

RESUMO

The cellular basis underlying the complex clinical symptomatology of bipolar disorder and the mechanisms underlying the actions of its effective treatments have not yet been fully elucidated. This study investigated the role of hippocampal synaptic AMPA receptors. We found that chronic administration of the antimanic agents lithium and valproate (VPA) reduced synaptic AMPA receptor GluR1/2 in hippocampal neurons in vitro and in vivo. Electrophysiological studies confirmed that the AMPA/NMDA ratio was reduced in CA1 regions of hippocampal slices from lithium-treated animals. Reduction in GluR1 phosphorylation at its cAMP-dependent protein kinase A site by the synthetic peptide TAT-S845, which mimics the effects of lithium or VPA, was sufficient to attenuate surface and synaptic GluR1/2 levels in hippocampal neurons in vitro and in vivo. Intrahippocampal infusion studies with the AMPA-specific inhibitor GYKI 52466 [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride], a GluR1-specific TAT-S845 peptide, showed that GluR1/2 was essential for the development of manic/hedonic-like behaviors such as amphetamine-induced hyperactivity. These studies provide novel insights into the role of hippocampal GluR1/2 receptors in mediating facets of the manic syndrome and offer avenues for the development of novel therapeutics for these disorders.


Assuntos
Transtorno Bipolar/patologia , Hipocampo/metabolismo , Receptores de AMPA/metabolismo , Animais , Antimaníacos/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzodiazepinas/farmacologia , Transtorno Bipolar/tratamento farmacológico , Células Cultivadas , Modelos Animais de Doenças , Embrião de Mamíferos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiologia , Hipocampo/ultraestrutura , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp/métodos , Ratos , Ratos Endogâmicos WKY , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Sinaptossomos/ultraestrutura , Ácido Valproico/farmacologia
7.
J Mol Neurosci ; 37(2): 123-34, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18677583

RESUMO

Valproate, an anticonvulsant and mood stabilizer, up-regulates Bcl-2, a neurotrophic/neuroprotective protein. In this study, we investigated the molecular mechanism through which Bcl-2 is up-regulated by valproate using cultured human neuron-like cells. Valproate, within therapeutically relevant ranges, induced time- and concentration-dependent up-regulations of both Bcl-2 messenger RNA and protein implicating an underlying gene transcriptional-mediated mechanism. Bcl-2 up-regulations were associated with ERK1/2 and PI3K pathway activations and elevated levels of activated phospho-RSK and phospho-CREB, convergent targets of the ERK1/2 and PI3K pathways. Valproate increased transcriptional activity of a human bcl-2 promoter-reporter gene construct. This effect was attenuated, but not blocked, by mutation of a CREB DNA binding site, a CRE site in the human bcl-2 promoter sequence. ERK and/or PI3K pathway inhibitors and RSK1 small hairpin RNA knockdown reduced, but did not abolish, baseline and valproate-induced promoter activities and lowered Bcl-2 protein levels. These data collectively suggest that valproate induces Bcl-2 regulation partially through activations of the ERK and PI3K cascades and their convergent kinase, RSK, although other unknown mechanism(s) are likely involved. Given the known roles of Bcl-2 in the central nervous system, the current findings offer a partial yet complex molecular mechanistic explanation for the known neurobiological effects of valproate including neurite growth, neuronal survival, and neurogenesis.


Assuntos
Anticonvulsivantes/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ácido Valproico/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Genes Reporter , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neuroblastoma , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Regiões Promotoras Genéticas , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo
8.
Bipolar Disord ; 11(4): 339-50, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19500087

RESUMO

OBJECTIVES: Several intracellular signaling cascades, such as the extracellular signal-regulated kinase (ERK), Wnt-signaling/GSK-3, PLC/PKC, and PI3K pathways, have been shown to be affected directly or indirectly by mood stabilizers. Clinical imaging studies reveal that mood disorders are associated with structural and/or metabolic changes in specific brain regions such as the anterior cingulate cortex (ACC). Here we investigated the extent to which perturbation of one of the affected pathways, the ERK pathway, in the ACC influences affective-related behavior. METHODS: The regional perturbation was induced by two means: local continuous infusion of PD98059, an ERK pathway inhibitor, and microinjection of a lentiviral-mediated gene delivery system encoding functional negative ERK1. The outcomes were monitored with a battery of affective-related tests similar to those used in several previous studies. RESULTS: Compared to their respective controls, rats infused with PD98059 or injected with the lentiviral negative ERK1 construct displayed hyperactivities in multiple tests, exhibited preferentially more open-arm activity in the elevated-plus-maze test, consumed more sweetened liquid in a saccharin preference test, and showed heightened response to amphetamine. CONCLUSIONS: These data support a role for the ACC ERK pathway in the regulation of affective-related behaviors. However, the medial prefrontal cortex (mPFC) comprises at least three other regions that will need to be similarly examined before specific roles of the ACC ERK pathway can be definitively attributed to affective behaviors. Additionally, responses of other signaling pathways to mood stabilizers in these mPFC regions, as well as the limbic regions to which they project, will be important to examine.


Assuntos
Comportamento Animal/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Giro do Cíngulo/metabolismo , Transdução de Sinais/fisiologia , Anfetamina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Estimulantes do Sistema Nervoso Central/farmacologia , Córtex Cerebral/citologia , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Giro do Cíngulo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Microinjeções/métodos , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mutação/genética , Neurônios , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Natação , Transfecção/métodos
9.
Elife ; 82019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31025938

RESUMO

It remains unclear to what extent neurodevelopmental disorder (NDD) risk genes retain functions into adulthood and how they may influence disease phenotypes. SYNGAP1 haploinsufficiency causes a severe NDD defined by autistic traits, cognitive impairment, and epilepsy. To determine if this gene retains therapeutically-relevant biological functions into adulthood, we performed a gene restoration technique in a mouse model for SYNGAP1 haploinsufficiency. Adult restoration of SynGAP protein improved behavioral and electrophysiological measures of memory and seizure. This included the elimination of interictal events that worsened during sleep. These events may be a biomarker for generalized cortical dysfunction in SYNGAP1 disorders because they also worsened during sleep in the human patient population. We conclude that SynGAP protein retains biological functions throughout adulthood and that non-developmental functions may contribute to disease phenotypes. Thus, treatments that target debilitating aspects of severe NDDs, such as medically-refractory seizures and cognitive impairment, may be effective in adult patients.


Assuntos
Envelhecimento/metabolismo , Comportamento , Encéfalo/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Potenciais de Ação , Animais , Comportamento Animal , Eletroencefalografia , Feminino , Humanos , Masculino , Memória , Camundongos , Camundongos Mutantes , Convulsões/metabolismo , Convulsões/fisiopatologia , Sono , Vigília
10.
Biol Psychiatry ; 77(9): 805-15, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25444158

RESUMO

BACKGROUND: Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders. METHODS: A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development. RESULTS: Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults. CONCLUSIONS: Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathologic process in developmental brain disorders.


Assuntos
Córtex Cerebral/anormalidades , Córtex Cerebral/crescimento & desenvolvimento , Haploinsuficiência , Células Piramidais/fisiologia , Proteínas Ativadoras de ras GTPase/deficiência , Proteínas Ativadoras de ras GTPase/genética , Animais , Animais Recém-Nascidos , Condicionamento Psicológico/fisiologia , Espinhas Dendríticas/patologia , Espinhas Dendríticas/fisiologia , Endofenótipos , Comportamento Exploratório/fisiologia , Medo/fisiologia , Hipocampo/anormalidades , Hipocampo/crescimento & desenvolvimento , Aprendizagem em Labirinto/fisiologia , Camundongos Transgênicos , Vias Neurais/anormalidades , Vias Neurais/crescimento & desenvolvimento , Células Piramidais/patologia , Privação Sensorial/fisiologia , Vibrissas/fisiologia
11.
Pharmacol Biochem Behav ; 75(1): 35-47, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12759111

RESUMO

Lithium is widely used in the management of bipolar disorder, yet memory impairment is a serious side effect. To assess the effects of lithium on spatial working and reference memories, we have employed a plus maze utilizing spontaneous alternation (SA) and place-learning paradigms in two experiments with the black molly fish. Four treatment groups were gavaged with 20 microl of a 10, 100, or 1000 mM lithium chloride (LiCl) solution or ddH(2)O vehicle every 12 h for 22 to 24 days. On Day 15, subjects began an 8-day SA task or a 10-day place-learning task. Results indicate that there is a significant difference in SA performance among the treatment groups for Days 1, 2, and 3. Results of the place-learning task indicate that the 1 M dose group needed significantly more trials to reach criterion and made significantly fewer correct first choices than the other dose groups. Capillary ion analysis determinations of plasma and brain lithium levels illustrate linear dose-response relationships to doses administered. Regression analyses indicate that there is a relationship between SA performance and plasma/brain lithium levels during the initial part of testing. Collectively, the results indicate that chronic lithium administration impairs spatial working and reference memories.


Assuntos
Antimaníacos/farmacologia , Lítio/farmacologia , Memória/efeitos dos fármacos , Poecilia/fisiologia , Percepção Espacial/efeitos dos fármacos , Animais , Antimaníacos/farmacocinética , Encéfalo/metabolismo , Aprendizagem por Discriminação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Alimentos , Lítio/sangue , Lítio/farmacocinética , Memória de Curto Prazo/efeitos dos fármacos , Reforço Psicológico
12.
Neuron ; 82(6): 1317-33, 2014 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-24945774

RESUMO

Syngap1 haploinsufficiency is a common cause of sporadic intellectual disability. Syngap1 mutations disrupt developing pyramidal neurons, although it remains unclear if this process contributes to cognitive abnormalities. Here, we found that haploinsufficiency restricted to forebrain glutamatergic neurons was sufficient to disrupt cognition and removing mutations from this population prevented cognitive abnormalities. In contrast, manipulating Syngap1 function in GABAergic neurons had no effect on cognition, excitability, or neurotransmission, highlighting the specificity of Syngap1 mutations within forebrain excitatory neurons. Interestingly, cognitive abnormalities were reliably predicted by the emergence of enhanced excitatory synaptic function in mature superficial cortical pyramidal cells, which was a neurophysiological disruption caused by Syngap1 dysfunction in developing, but not adult, forebrain neurons. We conclude that reduced cognition in Syngap1 mutants is caused by isolated damage to developing forebrain glutamatergic neurons. This damage triggers secondary disruptions to synaptic homeostasis in mature cortical pyramidal cells, which perpetuates brain dysfunction into adulthood.


Assuntos
Transtornos Cognitivos/genética , Potenciais Pós-Sinápticos Excitadores/genética , Mutação/genética , Neurônios/fisiologia , Prosencéfalo/crescimento & desenvolvimento , Proteínas Ativadoras de ras GTPase/genética , Animais , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/patologia , Prosencéfalo/patologia , Distribuição Aleatória
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