RESUMEN
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.
Asunto(s)
Proteínas del Citoesqueleto/deficiencia , Proteínas Activadoras de GTPasa/deficiencia , Discapacidades para el Aprendizaje/genética , Plasticidad Neuronal/fisiología , Proteínas Nucleares/deficiencia , Terminales Presinápticos/fisiología , Transducción de Señal/fisiología , Animales , Western Blotting , Condicionamiento Psicológico , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas del Citoesqueleto/genética , Estimulación Eléctrica , Proteínas Activadoras de GTPasa/genética , Discapacidades para el Aprendizaje/fisiopatología , Masculino , Ratones , Ratones Noqueados , Proteínas Nucleares/genéticaRESUMEN
Hyperpolarization-activated cyclic nucleotide modulated current (I(h)) sets resonance frequency within the θ-range (512 Hz) in pyramidal neurons. However, its precise contribution to the temporal fidelity of spike generation in response to stimulation of excitatory or inhibitory synapses remains unclear. In conditions where pharmacological blockade of I(h) does not affect synaptic transmission, we show that postsynaptic h-channels improve spike time precision in CA1 pyramidal neurons through two main mechanisms. I(h) enhances precision of excitatory postsynaptic potential (EPSP)--spike coupling because I(h) reduces peak EPSP duration. I(h) improves the precision of rebound spiking following inhibitory postsynaptic potentials (IPSPs) in CA1 pyramidal neurons and sets pacemaker activity in stratum oriens interneurons because I(h) accelerates the decay of both IPSPs and after-hyperpolarizing potentials (AHPs). The contribution of h-channels to intrinsic resonance and EPSP waveform was comparatively much smaller in CA3 pyramidal neurons. Our results indicate that the elementary mechanisms by which postsynaptic h-channels control fidelity of spike timing at the scale of individual neurons may account for the decreased theta-activity observed in hippocampal and neocortical networks when h-channel activity is pharmacologically reduced.
