RESUMO
In rodents, cortical interneurons originate from the medial ganglionic eminence (MGE) and caudal ganglionic eminence (CGE) according to precise temporal schedules. The mechanisms controlling the specification of CGE-derived interneurons and their role in cortical circuitry are still unknown. Here, we show that COUP-TFI expression becomes restricted to the dorsal MGE and CGE at embryonic day 13.5 in the basal telencephalon. Conditional loss of function of COUP-TFI in subventricular precursors and postmitotic cells leads to a decrease of late-born, CGE-derived, VIP (vasoactive intestinal peptide)- and CR (calretinin)-expressing bipolar cortical neurons, compensated by the concurrent increase of early-born MGE-derived, PV (parvalbumin)-expressing interneurons. Strikingly, COUP-TFI mutants are more resistant to pharmacologically induced seizures, a phenotype that is dependent on GABAergic signaling. Together, our data indicate that COUP-TFI controls the delicate balance between MGE- and CGE-derived cortical interneurons by regulating intermediate progenitor divisions and ultimately affecting the activity of the cortical inhibitory circuitry.
Assuntos
Fator I de Transcrição COUP/genética , Fator I de Transcrição COUP/fisiologia , Córtex Cerebral/fisiologia , Epilepsia/genética , Epilepsia/fisiopatologia , Interneurônios/fisiologia , Eminência Mediana/fisiologia , Animais , Antimetabólitos , Bromodesoxiuridina , Proliferação de Células , Córtex Cerebral/citologia , Convulsivantes/farmacologia , Resistência a Medicamentos/genética , Eletroencefalografia , Fenômenos Eletrofisiológicos , Epilepsia/induzido quimicamente , Imuno-Histoquímica , Hibridização In Situ , Eminência Mediana/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Receptores de GABA-A/genética , Receptores de GABA-A/fisiologia , Receptores de GABA-B/genética , Receptores de GABA-B/fisiologia , Telencéfalo/citologia , Telencéfalo/fisiologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
Patients with liver cirrhosis show disturbances in sleep and in its circadian rhythms which are an early sign of minimal hepatic encephalopathy (MHE). The mechanisms of these disturbances are poorly understood. Rats with porta-caval shunt (PCS), a model of MHE, show sleep disturbances reproducing those of cirrhotic patients. The aims of this work were to characterize the alterations in circadian rhythms in PCS rats and analyze the underlying mechanisms. To reach these aims, we analyzed in control and PCS rats: (a) daily rhythms of spontaneous and rewarding activity and of temperature, (b) timing of the onset of activity following turning-off the light, (c) synchronization to light after a phase advance and (d) the molecular mechanisms contributing to these alterations in circadian rhythms. PCS rats show altered circadian rhythms of spontaneous and rewarding activities (wheel running). PCS rats show more rest bouts during the active phase, more errors in the onset of motor activity and need less time to re-synchronize after a phase advance than control rats. Circadian rhythm of body temperature is also slightly altered in PCS rats. The internal period length (tau) of circadian rhythm of motor activity is longer in PCS rats. We analyzed some mechanisms by which hypothalamus modulate circadian rhythms. PCS rats show increased content of cGMP in hypothalamus while the activity of cGMP-dependent protein kinase was reduced by 41% compared to control rats. Altered cGMP-PKG pathway in hypothalamus would contribute to altered circadian rhythms and synchronization to light.