RESUMEN
Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic cortex (PL), a subdivision of PFC. In neonatal GE mice, sparser axonal projections from CA1 pyramidal neurons with decreased release probability reach the PL. Their ability to entrain layer 5/6 oscillatory activity and firing is decreased. These structural and functional deficits of hippocampal-prelimbic connectivity persist, yet are less prominent in prejuvenile GE mice. Thus, besides local dysfunction of HP and PL, weaker connectivity between the two brain areas is present in GE mice throughout development.SIGNIFICANCE STATEMENT Poor cognitive performance in mental disorders comes along with prefrontal-hippocampal dysfunction. Recent data from mice that model the psychiatric risk mediated by gene-environment (GE) interaction identified the origin of deficits during early development, when the local circuits in both areas are compromised. Here, we show that sparser and less efficient connectivity as well as cellular dysfunction are the substrate of the weaker excitatory drive from hippocampus (HP) to prefrontal cortex (PFC) as well as of poorer oscillatory coupling between the two brain areas in these mice. While the structural and functional connectivity deficits persist during the entire development, their magnitude decreases with age. The results add experimental evidence for the developmental miswiring hypothesis of psychiatric disorders.
Asunto(s)
Interacción Gen-Ambiente , Hipocampo/crecimiento & desarrollo , Trastornos Mentales/genética , Trastornos Mentales/fisiopatología , Red Nerviosa/crecimiento & desarrollo , Corteza Prefrontal/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Hipocampo/química , Masculino , Trastornos Mentales/psicología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/química , Corteza Prefrontal/química , Factores de RiesgoRESUMEN
Mutations in the gene of the peripheral myelin protein zero (P0) give rise to the peripheral neuropathies Charcot-Marie-Tooth type 1B disease (CMT1B), Déjérine-Sottas syndrome, and congenital hypomyelinating neuropathy. To investigate the pathomechanisms of a specific point mutation in the P0 gene, we generated two independent transgenic mouse lines expressing the pathogenic CMT1B missense mutation Ile106Leu (P0sub) under the control of the P0 promoter on a wild-type background. Both P0sub-transgenic mouse lines showed shivering and ultrastructural abnormalities including retarded myelination, onion bulb formation, and dysmyelination seen as aberrantly folded myelin sheaths and tomacula in all nerve fibers. Functionally, the mutation leads to dispersed compound muscle action potentials and severely reduced conduction velocities. Our observations support the view that the Ile106Leu mutation acts by a dominant-negative gain of function and that the P0sub-transgenic mouse represents an animal model for a severe, tomaculous form of CMT1B.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/patología , Proteína P0 de la Mielina/genética , Vaina de Mielina/patología , Nervios Periféricos/anomalías , Nervios Periféricos/patología , Potenciales de Acción/genética , Secuencia de Aminoácidos/genética , Sustitución de Aminoácidos , Animales , Enfermedad de Charcot-Marie-Tooth/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Genes Dominantes , Humanos , Ratones , Ratones Transgénicos , Microscopía Electrónica , Trastornos del Movimiento/genética , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/patología , Mutación Missense/genética , Vaina de Mielina/metabolismo , Vaina de Mielina/ultraestructura , Conducción Nerviosa/genética , Nervios Periféricos/ultraestructura , Regiones Promotoras Genéticas/genética , ARN Mensajero/metabolismoRESUMEN
The tenascin-R (TN-R) gene encodes a multidomain extracellular matrix glycoprotein belonging to the tenascin family. It is detectable mainly in oligodendrocytes and neuronal subpopulations of the central nervous system. In this report, we describe the structure of the 5'-region of the mouse TN-R gene and characterise the activity of its promoter. By in silico cloning and genome walking, we have deduced the organisation of the gene and identified the promoter sequence by 5'-RACE technology. TN-R transcripts in adult mouse brain contain non-coding exons 1 and 2 as demonstrated by the reverse transcriptase-polymerase chain reaction. The promoter displays its activity in cultured cells of neural origin, but not in a fibroblast-like cell line or an undifferentiated teratocarcimoma cell line. As for the human and rat genes, the elements required for the full and cell type-specific activity of the promoter are contained in exon 1 and 167 bp upstream of this exon. The mouse TN-R promoter sequence is similar to that of rat and human in that it displays similarly unusual features: it lacks any classical TATA-box or CAAT-box, GC-rich regions or initiator elements. The promoter contains consensus sequences for binding of a variety of transcription factors, notably p53/p73 and glucocorticoid receptors.
Asunto(s)
Regiones Promotoras Genéticas , Tenascina/genética , Animales , Secuencia de Bases , Encéfalo/embriología , Diferenciación Celular , Clonación Molecular , ADN Complementario/metabolismo , Proteínas de Unión al ADN/metabolismo , Exones , Fibroblastos/metabolismo , Genes Supresores de Tumor , Genoma , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Genéticos , Datos de Secuencia Molecular , Neuronas/metabolismo , Proteínas Nucleares/metabolismo , Reacción en Cadena de la Polimerasa , Unión Proteica , ARN Mensajero/metabolismo , Ratas , Receptores de Glucocorticoides/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Ácido Nucleico , Especificidad de la Especie , Transcripción Genética , Transfección , Células Tumorales Cultivadas , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de TumorRESUMEN
Cell adhesion molecules have been implicated in neural development and hippocampal synaptic plasticity. Here, we investigated the role of the neural cell adhesion molecule L1 in regulation of basal synaptic transmission and plasticity in the CA1 area of the hippocampus of juvenile mice. We show that theta-burst stimulation (TBS) and pairing of low-frequency presynaptic stimulation with depolarization of postsynaptic CA1 pyramidal cells induced similar levels of LTP in L1-deficient and wild-type mice. The basal excitatory synaptic transmission and density of asymmetric excitatory synapses in the stratum radiatum were also normal in L1-deficient mice. Since L1 is expressed not only by principal cells but also by inhibitory interneurons, we recorded inhibitory postsynaptic currents (IPSCs) evoked in CA1 pyramidal cells by minimal stimulation of perisomatic interneurons. L1-deficient mice showed a reduction in the mean amplitude of putative unitary IPSCs, higher values of the coefficient of amplitude variation, higher number of failures in transmitter release, and a reduction in frequency but not amplitude of miniature IPSCs. The use-dependent modulation of inhibitory transmission by paired-pulse or short tetanic stimulation was, however, normal in L1-deficient mice. The physiological abnormalities correlated with a strong reduction in the density of inhibitory active zones, indicating that L1 is involved in establishing inhibitory perisomatic synapses in the hippocampus.