RESUMEN
Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.
Asunto(s)
Anomalías Múltiples/genética , Duplicación Cromosómica/genética , Cognición , Discapacidad Intelectual/genética , Proteínas Nucleares/genética , Animales , Peso Corporal , Encéfalo/metabolismo , Encéfalo/ultraestructura , Deleción Cromosómica , Estructuras Cromosómicas/genética , Estructuras Cromosómicas/metabolismo , Cromosomas Humanos Par 17/genética , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Epigénesis Genética , Femenino , Eliminación de Gen , Reordenamiento Génico , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plasticidad Neuronal/genética , Proteínas Nucleares/metabolismo , Transmisión Sináptica/genética , Regulación hacia ArribaRESUMEN
Classical and systems genetics have identified wide networks of genes associated with cognitive and neurodevelopmental diseases. In parallel to deciphering the role of each of these genes in neuronal or synaptic function, evaluating the response of neuronal and molecular networks to gene loss of function could reveal some pathophysiological mechanisms potentially accessible to nongenetic therapies. Loss of function of the Rho-GAP oligophrenin-1 is associated with cognitive impairments in both human and mouse. Upregulation of both PKA and ROCK has been reported in Ophn1-/y mice, but it remains unclear whether kinase hyperactivity contributes to the behavioral phenotypes. In this study, we thoroughly characterized a prominent perseveration phenotype displayed by Ophn1-deficient mice using a Y-maze spatial working memory (SWM) test. We report that Ophn1 deficiency in the mouse generated severe cognitive impairments, characterized by both a high occurrence of perseverative behaviors and a lack of deliberation during the SWM test. In vivo and in vitro pharmacological experiments suggest that PKA dysregulation in the mPFC underlies cognitive dysfunction in Ophn1-deficient mice, as assessed using a delayed spatial alternation task results. Functionally, mPFC neuronal networks appeared to be affected in a PKA-dependent manner, whereas hippocampal-PFC projections involved in SWM were not affected in Ophn1-/y mice. Thus, we propose that discrete gene mutations in intellectual disability might generate "secondary" pathophysiological mechanisms, which are prone to become pharmacological targets for curative strategies in adult patients.SIGNIFICANCE STATEMENT Here we report that Ophn1 deficiency generates severe impairments in performance at spatial working memory tests, characterized by a high occurrence of perseverative behaviors and a lack of decision making. This cognitive deficit is consecutive to PKA deregulation in the mPFC that prevents Ophn1 KO mice to exploit a correctly acquired rule. Functionally, mPFC neuronal networks appear to be affected in a PKA-dependent manner, whereas behaviorally important hippocampal projections were preserved by the mutation. Thus, we propose that discrete gene mutations in intellectual disability can generate "secondary" pathophysiological mechanisms prone to become pharmacological targets for curative strategies in adults.
Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas del Citoesqueleto/deficiencia , Proteínas Activadoras de GTPasa/deficiencia , Trastornos de la Memoria/metabolismo , Memoria a Corto Plazo/fisiología , Proteínas Nucleares/deficiencia , Corteza Prefrontal/metabolismo , Animales , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Red Nerviosa/metabolismo , Red Nerviosa/fisiopatología , Técnicas de Cultivo de Órganos , Corteza Prefrontal/fisiopatología , Distribución AleatoriaRESUMEN
ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2(Camk2aCre/0) mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2(Camk2aCre/0) mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2(Camk2aCre/0) mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2(Camk2aCre/0) mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system.
Asunto(s)
Trastornos del Conocimiento/etiología , Proteínas de Drosophila/genética , Proteínas de la Membrana/genética , Degeneración Nerviosa/etiología , ATPasas de Translocación de Protón/genética , Receptores de Superficie Celular/genética , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Drosophila , Femenino , Técnicas de Silenciamiento del Gen , Discapacidad Intelectual/genética , Masculino , Ratones , Degeneración Nerviosa/patología , Neuronas/metabolismo , Neuronas/fisiología , Neuronas/ultraestructura , Trastornos Parkinsonianos/genética , Sinapsis/metabolismo , Sinapsis/fisiología , Sinapsis/ultraestructuraRESUMEN
Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic-AMP-protein kinase A-dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1-deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes.
Asunto(s)
Conducta Animal , Cognición/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Proteínas de Microfilamentos/fisiología , 4-Butirolactona/análogos & derivados , 4-Butirolactona/genética , Animales , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Memoria , Ratones , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Transducción de Señal , Conducta SocialRESUMEN
Intellectual disorders (IDs) have been regularly associated with morphological and functional deficits at glutamatergic synapses in both humans and rodents. How these synaptic deficits may lead to the variety of learning and memory deficits defining ID is still unknown. Here we studied the functional and behavioral consequences of the ID gene il1rapl1 deficiency in mice and reported that il1rapl1 constitutive deletion alters cued fear memory formation. Combined in vivo and in vitro approaches allowed us to unveil a causal relationship between a marked inhibitory/excitatory (I/E) imbalance in dedicated amygdala neuronal subcircuits and behavioral deficits. Cell-targeted recordings further demonstrated a morpho-functional impact of the mutation at thalamic projections contacting principal cells, whereas the same afferents on interneurons are unaffected by the lack of Il1rapl1. We thus propose that excitatory synapses have a heterogeneous vulnerability to il1rapl1 gene constitutive mutation and that alteration of a subset of excitatory synapses in neuronal circuits is sufficient to generate permanent cognitive deficits.
Asunto(s)
Potenciales Postsinápticos Excitadores/genética , Discapacidad Intelectual/complicaciones , Trastornos de la Memoria/etiología , Amígdala del Cerebelo/citología , Anestésicos Locales/farmacología , Animales , Aprendizaje por Asociación/fisiología , Corteza Cerebral/citología , Channelrhodopsins , Condicionamiento Psicológico/fisiología , Espinas Dendríticas/metabolismo , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Miedo/fisiología , Antagonistas del GABA/farmacología , Glutamato Descarboxilasa/genética , Proteínas Fluorescentes Verdes/genética , Técnicas In Vitro , Discapacidad Intelectual/genética , Proteína Accesoria del Receptor de Interleucina-1/genética , Proteína Accesoria del Receptor de Interleucina-1/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Inhibición Neural/efectos de los fármacos , Inhibición Neural/genética , Neuronas/fisiología , Neuronas/ultraestructuraRESUMEN
The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to environmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory formation, memory retrieval or behavioral expression deficits is not easy to establish. Here, we report some deficits in contextual fear behavior in knockout mice for the intellectual disability gene Il1rapl1. Functional in vivo experiments revealed that the lack of conditioned response resulted from a local inhibitory to excitatory (I/E) imbalance in basolateral amygdala (BLA) consecutive to a loss of excitatory drive onto BLA principal cells by caudal hippocampus axonal projections. A normalization of the fear behavior was obtained in adult mutant mice following opsin-based in vivo synaptic priming of hippocampo-BLA synapses in adult il1rapl1 knockout mice, indicating that synaptic efficacy at hippocampo-BLA projections is crucial for contextual fear memory expression. Importantly, because this restoration was obtained after the learning phase, our results suggest that some of the genetically encoded cognitive deficits in humans may originate from a lack of restitution of genuinely formed memories rather than an exclusive inability to store new memories.
Asunto(s)
Amígdala del Cerebelo/fisiología , Miedo/fisiología , Hipocampo/fisiología , Discapacidad Intelectual/fisiopatología , Proteína Accesoria del Receptor de Interleucina-1/fisiología , Animales , Condicionamiento Clásico/fisiología , Modelos Animales de Enfermedad , Discapacidad Intelectual/genética , Proteína Accesoria del Receptor de Interleucina-1/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Sinapsis/fisiología , Potenciales SinápticosRESUMEN
Loss-of-function mutations in the gene encoding for the RhoGAP protein of oligophrenin-1 (OPHN1) lead to cognitive disabilities (CDs) in humans, yet the underlying mechanisms are not known. Here, we show that in mice constitutive lack of Ophn1 is associated with dysregulation of the cyclic adenosine monophosphate/phosphate kinase A (cAMP/PKA) signalling pathway in a brain-area-specific manner. Consistent with a key role of cAMP/PKA signalling in regulating presynaptic function and plasticity, we found that PKA-dependent presynaptic plasticity was completely abolished in affected brain regions, including hippocampus and amygdala. At the behavioural level, lack of OPHN1 resulted in hippocampus- and amygdala-related learning disabilities which could be fully rescued by the ROCK/PKA kinase inhibitor fasudil. Together, our data identify OPHN1 as a key regulator of presynaptic function and suggest that, in addition to reported postsynaptic deficits, loss of presynaptic plasticity contributes to the pathophysiology of CDs.