RESUMEN
Output properties of neurons are greatly shaped by voltage-gated ion channels, whose biophysical properties and localization within axodendritic compartments serve to significantly transform the original input. The hyperpolarization-activated current, I(h), is mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and plays a fundamental role in influencing neuronal excitability by regulating both membrane potential and input resistance. In neurons such as cortical and hippocampal pyramidal neurons, the subcellular localization of HCN channels plays a critical functional role, yet mechanisms controlling HCN channel trafficking are not fully understood. Because ion channel function and localization are often influenced by interacting proteins, we generated a knock-out mouse lacking the HCN channel auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Eliminating expression of TRIP8b dramatically reduced I(h) expression in hippocampal pyramidal neurons. Loss of I(h)-dependent membrane voltage properties was attributable to reduction of HCN channels on the neuronal surface, and there was a striking disruption of the normal expression pattern of HCN channels in pyramidal neuron dendrites. In heterologous cells and neurons, absence of TRIP8b increased HCN subunit targeting to and degradation by lysosomes. Mice lacking TRIP8b demonstrated motor learning deficits and enhanced resistance to multiple tasks of behavioral despair with high predictive validity for antidepressant efficacy. We observed similar resistance to behavioral despair in distinct mutant mice lacking HCN1 or HCN2. These data demonstrate that interaction with the auxiliary subunit TRIP8b is a major mechanism underlying proper expression of HCN channels and I(h) in vivo, and suggest that targeting I(h) may provide a novel approach to treatment of depression.
Asunto(s)
Canales Catiónicos Regulados por Nucleótidos Cíclicos/deficiencia , Canales Catiónicos Regulados por Nucleótidos Cíclicos/metabolismo , Depresión/genética , Eliminación de Gen , Hipocampo/fisiología , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/metabolismo , Canales de Potasio/deficiencia , Canales de Potasio/metabolismo , Subunidades de Proteína/metabolismo , Animales , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Depresión/psicología , Depresión/terapia , Terapia Genética/métodos , Hipocampo/química , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Peroxinas , Canales de Potasio/genética , Subunidades de Proteína/deficiencia , Subunidades de Proteína/fisiología , Transporte de Proteínas/genéticaRESUMEN
Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.
Asunto(s)
Región CA1 Hipocampal/fisiología , Región CA3 Hipocampal/fisiología , Corteza Entorrinal/fisiología , Potenciales de la Membrana/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Células Piramidales/fisiología , Navegación Espacial/fisiología , Animales , Conducta Animal/fisiología , Región CA1 Hipocampal/citología , RatonesRESUMEN
Spatial and temporal features of synaptic inputs engage integration mechanisms on multiple scales, including presynaptic release sites, postsynaptic dendrites, and networks of inhibitory interneurons. Here we investigate how these mechanisms cooperate to filter synaptic input in hippocampal area CA1. Dendritic recordings from CA1 pyramidal neurons reveal that proximal inputs from CA3 as well as distal inputs from entorhinal cortex layer III (ECIII) sum sublinearly or linearly at low firing rates due to feedforward inhibition, but sum supralinearly at high firing rates due to synaptic facilitation, producing a high-pass filter. However, during ECIII and CA3 input comparison, supralinear dendritic integration is dynamically balanced by feedforward and feedback inhibition, resulting in suppression of dendritic complex spiking. We find that a particular subpopulation of CA1 interneurons expressing neuropeptide Y (NPY) contributes prominently to this dynamic filter by integrating both ECIII and CA3 input pathways and potently inhibiting CA1 pyramidal neuron dendrites.
Asunto(s)
Potenciales de Acción/fisiología , Región CA1 Hipocampal/fisiología , Interneuronas/fisiología , Red Nerviosa/fisiología , Inhibición Neural/fisiología , Animales , Técnicas de Sustitución del Gen/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , RatasRESUMEN
Timing is a crucial aspect of synaptic integration. For pyramidal neurons that integrate thousands of synaptic inputs spread across hundreds of microns, it is thus a challenge to maintain the timing of incoming inputs at the axo-somatic integration site. Here we show that pyramidal neurons in the rodent hippocampus use a gradient of inductance in the form of hyperpolarization-activated cation-nonselective (HCN) channels as an active mechanism to counteract location-dependent temporal differences of dendritic inputs at the soma. Using simultaneous multi-site whole-cell recordings complemented by computational modeling, we find that this intrinsic biophysical mechanism produces temporal synchrony of rhythmic inputs in the theta and gamma frequency ranges across wide regions of the dendritic tree. While gamma and theta oscillations are known to synchronize activity across space in neuronal networks, our results identify a new mechanism by which this synchrony extends to activity within single pyramidal neurons with complex dendritic arbors.