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The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons receives substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch recordings demonstrated that the amplitude and properties of ensemble HCN channel activity were uniform in patches excised from distal apical dendritic trunk and tuft sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamic-clamp experiments revealed that these compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B pyramidal neurons.

Under certain conditions, regenerative voltage spikes can be initiated locally in the dendrites of CA1 pyramidal neurons. These are interesting events that could potentially provide neurons with additional computational abilities. Using whole-cell dendritic recordings from the distal apical trunk and proximal tuft regions and realistic computer modeling, we have determined that highly synchronized and moderately clustered inputs are required for dendritic spike initiation: ∼50 synaptic inputs spread over 100 μm of the apical trunk/tuft need to be activated within 3 msec. Dendritic spikes are characterized by a more depolarized voltage threshold than at the soma [-48 ± 1 mV (n= 30) vs -56 ± 1 mV (n= 7), respectively] and are mainly generated and shaped by dendritic Na+and K+currents. The relative contribution of AMPA and NMDA currents is also important in determining the actual spatiotemporal requirements for dendritic spike initiation. Once initiated, dendritic spikes can easily reach the soma, but their propagation is only moderately strong, so that it can be modulated by physiologically relevant factors such as changes in theVmand the ionic composition of the extracellular solution. With effective spike propagation, an extremely short-latency neuronal output is produced for greatly reduced input levels. Therefore, dendritic spikes function as efficient detectors of specific input patterns, ensuring that the neuronal response to high levels of input synchrony is a precisely timed action potential output.

Step hyperpolarizations evoked slowly activating, noninactivating, and slowly deactivating inward currents from membrane patches recorded in the cell-attached patch configuration from the soma and apical dendrites of hippocampal CA1 pyramidal neurons. The density of these hyperpolarization-activated currents (Ih) increased over sixfold from soma to distal dendrites. Activation curves demonstrate that a significant fraction ofIhchannels is active near rest and that the range is hyperpolarized relatively more in the distal dendrites.Ihactivation and deactivation kinetics are voltage-and temperature-dependent, with time constants of activation and deactivation decreasing with hyperpolarization and depolarization, respectively.Ihdemonstrated a mixed Na+–K+conductance and was sensitive to low concentrations of external CsCl. Dual whole-cell recordings revealed regional differences in input resistance (Rin) and membrane polarization rates (τmem) across the somatodendritic axis that are attributable to the spatial gradient ofIhchannels. As a result of these membrane effects the propagation of subthreshold voltage transients is directionally specific. The elevated dendriticIhdensity decreases EPSP amplitude and duration and reduces the time window over which temporal summation takes place. The backpropagation of action potentials into the dendritic arborization was impacted only slightly by dendriticIh, with the most consistent effect being a decrease in dendritic action potential duration and an increase in afterhyperpolarization. Overall,Ihacts to dampen dendritic excitability, but its largest impact is on the subthreshold range of membrane potentials where the integration of inhibitory and excitatory synaptic inputs takes place.

Although the function of sleep remains elusive, several lines of evidence suggest that sleep has an important role in learning and memory. In light of the available data and with the prevalence of sleep deprivation (SD), we sought to determine the effect of SD on neuronal functioning. We found that the exposure of rats to 72 hr of primarily rapid eye movement SD impaired their subsequent performance on a hippocampus-dependent spatial learning task but had no effect on an amygdala-dependent learning task. To determine the underlying cellular level mechanisms of this hippocampal deficit, we examined the impact of SD on several fundamental aspects of membrane excitability and synaptic physiology in hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. We found that neuronal excitability was severely reduced in CA1 neurons but not in granule cells and that the production of long-term potentiation of synaptic strength was inhibited in both areas. Using multiple SD methods we further attempted to differentiate the effects of sleep deprivation from those associated with the nonspecific stress induced by the sleep deprivation methods. Together these data suggest that failure to acquire adequate sleep produces several molecular and cellular level alterations that profoundly inhibit hippocampal functioning.