RESUMEN
Approximately one in 45 children have been diagnosed with Autism Spectrum Disorder (ASD), which is characterized by social/communication impairments. Recent studies have linked a subset of familial ASD to mutations in the Protocadherin 10 (Pcdh10) gene. Additionally, Pcdh10's expression pattern, as well as its known role within protein networks, implicates the gene in ASD. Subsequently, the neurobiology of mice heterozygous for Pcdh10 (Pcdh10+/-) has been investigated as a proxy for ASD. Male Pcdh10+/- mice have demonstrated sex-specific deficits in social behavior, recapitulating the gender bias observed in ASD. Furthermore, in vitro slice preparations of these Pcdh10+/- mice demonstrate selective decreases to high frequency electrophysiological responses, mimicking clinical observations. The direct in vivo ramifications of such decreased in vitro high frequency responses are unclear. As such, Pcdh10+/- mice and their wild-type (WT) littermates underwent in vivo electrocorticography (ECoG), as well as ex vivo amino acid concentration quantification using High Performance Liquid Chromatography (HPLC). Similar to the previously observed reductions to in vitro high frequency electrophysiological responses in Pcdh10+/- mice, male Pcdh10+/- mice exhibited reduced gamma-band (30-80Hz), but not lower frequency (10 and 20Hz), auditory steady state responses (ASSR). In addition, male Pcdh10+/- mice exhibited decreased signal-to-noise-ratio (SNR) for high gamma-band (60-100Hz) activity. These gamma-band perturbations for both ASSR and SNR were not observed in females. Administration of a GABAB agonist remediated these electrophysiological alterations among male Pcdh10+/-mice. Pcdh10+/- mice demonstrated increased concentrations of GABA and glutamine. Of note, a correlation of auditory gamma-band responses with underlying GABA concentrations was observed in WT mice. This correlation was not present in Pcdh10+/- mice. This study demonstrates the role of Pcdh10 in the regulation of excitatory-inhibitory balance as a function of GABA in ASD.
Asunto(s)
Baclofeno/farmacología , Cadherinas/metabolismo , Agonistas de Receptores GABA-B/farmacología , Ritmo Gamma/efectos de los fármacos , Ritmo Gamma/fisiología , Ácido gamma-Aminobutírico/metabolismo , Estimulación Acústica , Animales , Percepción Auditiva/efectos de los fármacos , Percepción Auditiva/fisiología , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Cadherinas/genética , Cromatografía Líquida de Alta Presión , Electrocorticografía , Electrodos Implantados , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Femenino , Glutamina/metabolismo , Masculino , Ratones Transgénicos , Protocadherinas , Caracteres Sexuales , Ritmo Teta/efectos de los fármacos , Ritmo Teta/fisiologíaRESUMEN
Highly topographic organization of neural circuits exists for the regulation of various brain functions in corticobasal ganglia circuits. Although neural circuit-specific refinement during synapse development is essential for the execution of particular neural functions, the molecular and cellular mechanisms for synapse refinement are largely unknown. Here, we show that protocadherin 17 (PCDH17), one of the nonclustered δ2-protocadherin family members, is enriched along corticobasal ganglia synapses in a zone-specific manner during synaptogenesis and regulates presynaptic assembly in these synapses. PCDH17 deficiency in mice causes facilitated presynaptic vesicle accumulation and enhanced synaptic transmission efficacy in corticobasal ganglia circuits. Furthermore, PCDH17(-/-) mice exhibit antidepressant-like phenotypes that are known to be regulated by corticobasal ganglia circuits. Our findings demonstrate a critical role for PCDH17 in the synaptic development of specific corticobasal ganglia circuits and suggest the involvement of PCDH17 in such circuits in depressive behaviors.
Asunto(s)
Ganglios Basales/citología , Cadherinas/fisiología , Corteza Cerebral/citología , Neuronas/fisiología , Terminales Presinápticos/fisiología , Sinapsis/genética , Estimulación Acústica , Animales , Animales Recién Nacidos , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Transformada , Condicionamiento Psicológico/fisiología , Cricetinae , Cricetulus , Homólogo 4 de la Proteína Discs Large , Conducta Exploratoria , Miedo/fisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Guanilato-Quinasas/metabolismo , Suspensión Trasera/fisiología , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Aprendizaje por Laberinto/fisiología , Potenciales de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Microscopía Electrónica , Red Nerviosa/fisiología , Neuronas/metabolismo , Neuronas/ultraestructura , Técnicas de Placa-Clamp , Protocadherinas , Natación/fisiología , Sinapsis/metabolismo , Sinapsis/ultraestructura , Transmisión Sináptica/genética , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/ultraestructura , Proteínas de Transporte Vesicular de Glutamato/metabolismoRESUMEN
The ventral telencephalon in the embryonic brain is thought to provide guidance cues for navigation of thalamocortical axons, but the mechanisms involved remain largely elusive. OL-protocadherin (OL-pc), a member of the cadherin superfamily, is highly expressed by striatal neurons in the developing ventral telencephalon. Here we show that OL-pc-deficient (Pcdh10(-/-)) mice have defects in axon pathways through the ventral telencephalon; for example, thalamocortical and corticothalamic projections cannot cross the ventral telencephalon. In the ventral telencephalon, striatal axons fail to grow out, and, concomitantly, the caudal portion of the globus pallidus and the associated 'corridor' thought to be important for thalamocortical fiber navigation do not form. The inability of the striatum to extend axons is also observed in vitro. These results show that OL-pc is essential for both elongation of striatal axons and patterning of the putative guidance cues for thalamocortical projections.