Dynamic modification of dendritic cable properties and synaptic transmission by voltage-gated potassium channels

Computer simulations of a dendrite possessing voltage-sensitive potassium conductances were used to determine the effects of these conductances on synaptic transmission and on the propagation of synaptic signals within the dendritic tree. Potassium conductances had two principal effects on voltage transients generated by current injections or synaptic conductances. Locally (near the source of the transient), voltage-gated potassium channels produced a potassium shunt current that reduced the amplitude of voltage transients generated by depolarizing currents. This shunt current increased as the amplitude of the depolarizing transient increased and so acted to prevent large synaptic transients from reaching levels that would saturate due to a reduction in driving force. In the presence of rapidly activating potassium currents, excitatory synapses produced larger synaptic currents that were more linearly related to synaptic conductance, but these produced smaller voltage transients. The maximum amplitudes of the voltage transients were limited by the voltage sensitivity of the K⁺ conductance and the rate at which it could activate. Sufficiently rapid synaptic currents could outrun the K⁺ conductance and thus achieve high local peak amplitudes. These effects of K⁺ conductances were unrelated to whether they were located on dendrites or not, being related only to their proximity to the source of synaptic current. The second class of effects of K⁺ conductances depended on their alteration of the electrotonic structure of the postsynaptic cell and so were observed only when they were located on postsynaptic dendrites. Voltage-gated K⁺ conductances produced voltage-dependent electrotonic expansion of depolarized dendrites, which had the effect of isolating synaptic inputs on depolarized dendrites from events on the rest of the neuron. Thus, synapses on the same dendrite interacted destructively to a degree much greater than that expected from the classical driving force nonlinearity. Synapses located proximally to a depolarized dendritic region were less effected than those located distally, and the range of the nonlinear interaction between synapses was dependent on the kinetics of activation and deactivation of the conductance. When present in conjunction with rapidly activating dendritic sodium conductance, the potassium conductance sharpened the requirement for spatial and temporal coincidence to produce synaptic boosting by inward currents, and suppressed out-of-synchrony synaptic inputs.     

Spatial Localization of Synapses Required for Supralinear Summation of Action Potentials and EPSPs

Although the supralinear summation of synchronizing excitatory postsynaptic potentials (EPSPs) and backpropagating action potentials (APs) is important for spike-timing-dependent synaptic plasticity (STDP), the spatial conditions of the amplification in the divergent dendritic structure have yet to be analyzed. In the present study, we simulated the coincidence of APs with EPSPs at randomly determined synaptic sites of a morphologically reconstructed hippocampal CA1 pyramidal model neuron and clarified the spatial condition of the amplifying synapses. In the case of uniform conductance inputs, the amplifying synapses were localized in the middle apical dendrites and distal basal dendrites with small diameters, and the ratio of synapses was unexpectedly small: 8-16% in both apical and basal dendrites. This was because the appearance of strong amplification requires the coincidence of both APs of 3-30 mV and EPSPs of over 6 mV, both of which depend on the dendritic location of synaptic sites. We found that the localization of amplifying synapses depends on A-type K+ channel distribution because backpropagating APs depend on the A-type K+ channel distribution, and that the localizations of amplifying synapses were similar within a range of physiological synaptic conductances. We also quantified the spread of membrane amplification in dendrites, indicating that the neighboring synapses can also show the amplification. These findings allowed us to computationally illustrate the spatial localization of synapses for supralinear summation of APs and EPSPs within thin dendritic branches where patch clamp experiments cannot be easily conducted.     

Role of active dendritic conductances in subthreshold input integration

Dendrites of many types of neurons contain voltage-dependent conductances that are active at subthreshold membrane potentials. To understand the computations neurons perform it is key to understand the role of active dendrites in the subthreshold processing of synaptic inputs. We examine systematically how active dendritic conductances affect the time course of postsynaptic potentials propagating along dendrites, and how they affect the interaction between such signals. Voltage-dependent currents can be classified into two types that have qualitatively different effects on subthreshold input responses: regenerative dendritic currents boost and broaden EPSPs, while restorative currents attenuate and narrow EPSPs. Importantly, the effects of active dendritic currents on EPSP shape increase as the EPSP travels along the dendrite. The effectiveness of active currents in modulating the EPSP shape is determined by their activation time constant: the faster it is, the stronger the effect on EPSP amplitude, while the largest effects on EPSP width occur when it is comparable to the membrane time constant. We finally demonstrate that the two current types can differentially improve precision and robustness of neural computations: restorative currents enhance coincidence detection of dendritic inputs, whereas direction selectivity to sequences of dendritic inputs is enhanced by regenerative dendritic currents.     

Computational simulation of the input-output relationship in hippocampal pyramidal cells

The precise mapping of how complex patterns of synaptic inputs are integrated into specific patterns of spiking output is an essential step in the characterization of the cellular basis of network dynamics and function. Relative to other principal neurons of the hippocampus, the electrophysiology of CA1 pyramidal cells has been extensively investigated. Yet, the precise input-output relationship is to date unknown even for this neuronal class. CA1 pyramidal neurons receive laminated excitatory inputs from three distinct pathways: recurrent CA1 collaterals on basal dendrites, CA3 Schaffer collaterals, mostly on oblique and proximal apical dendrites, and entorhinal perforant pathway on distal apical dendrites. We implemented detailed computer simulations of pyramidal cell electrophysiology based on three-dimensional anatomical reconstructions and compartmental models of available biophysical properties from the experimental literature. To investigate the effect of synaptic input on axosomatic firing, we stochastically distributed a realistic number of excitatory synapses in each of the three dendritic layers. We then recorded the spiking response to different stimulation patterns. For all dendritic layers, synchronous stimuli resulted in trains of spiking output and a linear relationship between input and output firing frequencies. In contrast, asynchronous stimuli evoked non-bursting spike patterns and the corresponding firing frequency input-output function was logarithmic. The regular/irregular nature of the input synaptic intervals was only reflected in the regularity of output inter-burst intervals in response to synchronous stimulation, and never affected firing frequency. Synaptic stimulations in the basal and proximal apical trees across individual neuronal morphologies yielded remarkably similar input-output relationships. Results were also robust with respect to the detailed distributions of dendritic and synaptic conductances within a plausible range constrained by experimental evidence. In contrast, the input-output relationship in response to distal apical stimuli showed dramatic differences from the other dendritic locations as well as among neurons, and was more sensible to the exact channel densities. Action Editor: Alain Destexhe     

Emerging methodologies for the study of hypothalamic gonadotropin-releasing-hormone (GnRH) neurons

Gonadotropin-releasing-hormone (GnRH) neurons form part of a central neural oscillator that controls sexual reproduction through intermittent release of the GnRH peptide. Activity of GnRH neurons, and by extension release of GnRH, has been proposed to reflect intrinsic properties and synaptic input of GnRH neurons. To study GnRH neurons, we used traditional electrophysiology and computational methods. These emerging methodologies enhance the elucidation of processing in GnRH neurons. We used dynamic current-clamping to understand how living GnRH somata process input from glutamate and GABA, two key neurotransmitters in the neuroendocrine hypothalamus. In order to study the impact of synaptic integration in dendrites and neuronal morphology, we have developed full-morphology models of GnRH neurons. Using dynamic clamping, we have demonstrated that small-amplitude glutamatergic currents can drive repetitive firing in GnRH neurons. Furthermore, application of simulated GABAergic synapses with a depolarized reversal potential have revealed two functional subpopulations of GnRH neurons: one population in which GABA chronically depolarizes membrane potential (without inducing action potentials) and a second population in which GABAergic excitation results in slow spiking. Finally, when AMPA-type and GABA-type simulated inputs are applied together, action potentials occur when the AMPA-type conductance occurs during the descending phase of GABAergic excitation and at the nadir of GABAergic inhibition. Compartmental computer models have shown that excitatory synapses at >300 microns from somtata are unable to drive spiking with purely passive dendrites. In models with active dendrites, distal synapses are more efficient at driving spiking than somatic inputs. We then used our models to extend the results from dynamic current clamping at GnRH somata to distribute synaptic inputs along the dendrite. We show that propagation delays for dendritic synapses alter synaptic integration in GnRH neurons by widening the temporal window of interaction for the generation of action potentials. Finally, we have shown that changes in dendrite morphology can modulate the output of GnRH neurons by altering the efficacy of action potential generation in response to after-depolarization potentials (ADPs). Taken together, the methodologies of dynamic current clamping and multi-compartmental modeling can make major contributions to the study of synaptic integration and structure-function relationships in hypothalamic GnRH neurons. Use of these methodological approaches will continue to provide keen insights leading to conceptual advances in our understanding of reproductive hormone secretion in normal and pathological physiology and open the door to understanding whether the mechanisms of pulsatile GnRH release are conserved across species.     

Geometry-induced features of current transfer in neuronal dendrites with tonically activated conductances

The impact of dendritic geometry on somatopetal transfer of the current generated by steady uniform activation of excitatory synaptic conductance distributed over passive, or active (Hodgkin-Huxley type), dendrites was studied in simulated neurons. Such tonic activation was delivered to the uniform dendrite and to the dendrites with symmetric or asymmetric branching with various ratios of branch diameters. Transfer effectiveness of the dendrites with distributed sources was estimated by the core current increment directly related to the total membrane current per unit path length. The effectiveness decreased with increasing path distance from the soma along uniform branches. The primary reason for this was the asymmetry of somatopetal vs somatofugal input core conductance met by synaptic current due to a greater leak conductance at the proximal end of the dendrite. Under these conditions, an increasing somatopetal core current and a corresponding drop of the depolarization membrane potential occurred. The voltage-dependent extrasynaptic conductances, if present, followed this depolarization. Consequently, the driving potential and membrane current densities decreased with increasing path distance from the soma. All path profiles were perturbed at bifurcations, being identical in symmetrical branches and diverging in asymmetrical ones. These perturbations were caused by voltage gradient breaks (abrupt change in the profile slope) occurring at the branching node due to coincident inhomogeneity of the dendritic core cross-section area and its conductance. The gradient was greater on the side of the smaller effective cross-section. Correspondingly, the path profiles of the somatopetal current transfer effectiveness were broken and/or diverged. The dendrites, their paths, and sites which were more effective in the current transfer from distributed sources were also more effective in the transfer from single-site inputs. The effectiveness of the active dendrite depended on the activation-inactivation kinetics of its voltage-gated conductances. In particular, dendrites with the same geometry were less effective with the Hodgkin-Huxley membrane than with the passive membrane, because of the effect of the noninactivating K⁺-conductance associated with the hyperpolarization equilibrium potential. Such electrogeometrical coupling may form a basis for path-dependent input-output conversion in the dendritic neurons, as the output discharge rate is defined by the net current delivered to the soma. Received: 18 December 1997 / Accepted in revised form: 12 June 1998     

Synaptic integration in dendritic trees

Most neurons have elaborate dendritic trees that receive tens of thousands of synaptic inputs. Because postsynaptic responses to individual synaptic events are usually small and transient, the integration of many synaptic responses is needed to depolarize most neurons to action potential threshold. Over the past decade, advances in electrical and optical recording techniques have led to new insights into how synaptic responses propagate and interact within dendritic trees. In addition to their passive electrical and morphological properties, dendrites express active conductances that shape individual synaptic responses and influence synaptic integration locally within dendrites. Dendritic voltage-gated Na(+) and Ca(2+) channels support action potential backpropagation into the dendritic tree and local initiation of dendritic spikes, whereas K(+) conductances act to dampen dendritic excitability. While all dendrites investigated to date express active conductances, different neuronal types show specific patterns of dendritic channel expression leading to cell-specific differences in the way synaptic responses are integrated within dendritic trees. This review explores the way active and passive dendritic properties shape synaptic responses in the dendrites of central neurons, and emphasizes their role in synaptic integration.     

Dendritic spikes and activity-dependent synaptic plasticity

Whereas the regenerative nature of action potential conduction in axons has been known since the late 1940s, neuronal dendrites have been considered as passive cables transferring incoming synaptic activity to the soma. The relatively recent discovery that neuronal dendrites contain active conductances has revolutionized our view of information processing in neurons. In many neuronal cell types, sodium action potentials initiated at the axon initial segment can back-propagate actively into the dendrite thereby serving, for the dendrite, as an indicator of the output activity of the neuron. In addition, the dendrites themselves can initiate action-potential-like regenerative responses, so-called dendritic spikes, that are mediated either by the activation of sodium, calcium, and/or N-methyl-D-aspartate receptor channels. Here, we review the recent experimental and theoretical evidence for a role of regenerative dendritic activity in information processing within neurons and, especially, in activity-dependent synaptic plasticity.     

Imperfect space clamp permits electrotonic interactions between inhibitory and excitatory synaptic conductances, distorting voltage clamp recordings

The voltage clamp technique is frequently used to examine the strength and composition of synaptic input to neurons. Even accounting for imperfect voltage control of the entire cell membrane ("space clamp"), it is often assumed that currents measured at the soma are a proportional indicator of the postsynaptic conductance. Here, using NEURON simulation software to model somatic recordings from morphologically realistic neurons, we show that excitatory conductances recorded in voltage clamp mode are distorted significantly by neighboring inhibitory conductances, even when the postsynaptic membrane potential starts at the reversal potential of the inhibitory conductance. Analogous effects are observed when inhibitory postsynaptic currents are recorded at the reversal potential of the excitatory conductance. Escape potentials in poorly clamped dendrites reduce the amplitude of excitatory or inhibitory postsynaptic currents recorded at the reversal potential of the other conductance. In addition, unclamped postsynaptic inhibitory conductances linearize the recorded current-voltage relationship of excitatory inputs comprising AMPAR and NMDAR-mediated components, leading to significant underestimation of the relative contribution by NMDARs, which are particularly sensitive to small perturbations in membrane potential. Voltage clamp accuracy varies substantially between neurons and dendritic arbors of different morphology; as expected, more reliable recordings are obtained from dendrites near the soma, but up to 80% of the synaptic signal on thin, distant dendrites may be lost when postsynaptic interactions are present. These limitations of the voltage clamp technique may explain how postsynaptic effects on synaptic transmission could, in some cases, be attributed incorrectly to presynaptic mechanisms.     

Spatial Distribution of Excitatory Synapses on the Dendrites of Ganglion Cells in the Mouse Retina

Excitatory glutamatergic inputs from bipolar cells affect the physiological properties of ganglion cells in the mammalian retina. The spatial distribution of these excitatory synapses on the dendrites of retinal ganglion cells thus may shape their distinct functions. To visualize the spatial pattern of excitatory glutamatergic input into the ganglion cells in the mouse retina, particle-mediated gene transfer of plasmids expressing postsynaptic density 95-green fluorescent fusion protein (PSD95-GFP) was used to label the excitatory synapses. Despite wide variation in the size and morphology of the retinal ganglion cells, the expression of PSD95 puncta was found to follow two general rules. Firstly, the PSD95 puncta are regularly spaced, at 1–2 µm intervals, along the dendrites, whereby the presence of an excitatory synapse creates an exclusion zone that rules out the presence of other glutamatergic synaptic inputs. Secondly, the spatial distribution of PSD95 puncta on the dendrites of diverse retinal ganglion cells are similar in that the number of excitatory synapses appears to be less on primary dendrites and to increase to a plateau on higher branch order dendrites. These observations suggest that synaptogenesis is spatially regulated along the dendritic segments and that the number of synaptic contacts is relatively constant beyond the primary dendrites. Interestingly, we also found that the linear puncta density is slightly higher in large cells than in small cells. This may suggest that retinal ganglion cells with a large dendritic field tend to show an increased connectivity of excitatory synapses that makes up for their reduced dendrite density. Mapping the spatial distribution pattern of the excitatory synapses on retinal ganglion cells thus provides explicit structural information that is essential for our understanding of how excitatory glutamatergic inputs shape neuronal responses.     

Motoneuron dendrites: role in synaptic integration.

Dendrites constitute over 80 per cent of the receptive surface area in cat motoneurons. Calculations based on matched electrical and gemoetrical measurements in these neurons indicate that the specific resistance of dendritic membranes in resting motoneurons is at least 2,000 ohm-cm2. When the specific membrane resistance is this high, even the most distal dendritic synapses can contribute significantly to the depolarization of the soma, and hence influence the rate of action potential generation. However, dendritic membrane resistance depends strongly on the level of background synaptic activity. The conductance changes associated with excitatory synaptic activity on a dendrite can be great enough to reduce significantly both the excitatory synaptic driving potential and the effective membrane resistance on that dendrite, and thus greatly reduce the effectiveness of synapses on the dendrite. Inhibitory synaptic activity produces an even greater reduction in dendritic membrane resistance. Thus the relative effectiveness of dendritic synapses depends on the type, distribution, and intensity of background synaptic activity, as well as on dendritic geometry and resting membrane properties.     

Modulation of synaptic potentials and cell excitability by dendritic K<Subscript>IR</Subscript> and K<Subscript>As</Subscript> channels in nucleus accumbens medium spiny neurons: A computational study

The nucleus accumbens (NAc), a critical structure of the brain reward circuit, is implicated in normal goal-directed behaviour and learning as well as pathological conditions like schizophrenia and addiction. Its major cellular substrates, the medium spiny (MS) neurons, possess a wide variety of dendritic active conductances that may modulate the excitatory post synaptic potentials (EPSPs) and cell excitability. We examine this issue using a biophysically detailed 189-compartment stylized model of the NAc MS neuron, incorporating all the known active conductances. We find that, of all the active channels, inward rectifying K⁺ (K_IR) channels play the primary role in modulating the resting membrane potential (RMP) and EPSPs in the down-state of the neuron. Reduction in the conductance of K_IR channels evokes facilitatory effects on EPSPs accompanied by rises in local input resistance and membrane time constant. At depolarized membrane potentials closer to up-state levels, the slowly inactivating A-type potassium channel (K_As) conductance also plays a strong role in determining synaptic potential parameters and cell excitability. We discuss the implications of our results for the regulation of accumbal MS neuron biophysics and synaptic integration by intrinsic factors and extrinsic agents such as dopamine.     

Signal integration on the dendrites of a pyramidal neuron model

This paper studied the synaptic and dendritic integration with different spatial distributions of synapses on the dendrites of a biophysically-detailed layer 5 pyramidal neuron model. It has been observed that temporally synchronous and spatially clustered synaptic inputs make dendrites perform a highly nonlinear integration. The effect of clustering degree of synaptic distribution on neuronal responsiveness is investigated by changing the number of top apical dendrites where active synapses are allocated. The neuron shows maximum responsiveness to synaptic inputs which have an intermediate clustering degree of spatial distribution, indicating complex interactions among dendrites with the existence of nonlinear synaptic and dendritic integrations.     

Nonlinear regulation of unitary synaptic signals by CaV(2.3) voltage-sensitive calcium channels located in dendritic spines

The roles of voltage-sensitive sodium (Na) and calcium (Ca) channels located on dendrites and spines in regulating synaptic signals are largely unknown. Here we use 2-photon glutamate uncaging to stimulate individual spines while monitoring uncaging-evoked excitatory postsynaptic potentials (uEPSPs) and Ca transients. We find that, in CA1 pyramidal neurons in acute mouse hippocampal slices, CaV(2.3) voltage-sensitive Ca channels (VSCCs) are found selectively on spines and act locally to dampen uncaging-evoked Ca transients and somatic potentials. These effects are mediated by a regulatory loop that requires opening of CaV(2.3) channels, voltage-gated Na channels, small conductance Ca-activated potassium (SK) channels, and NMDA receptors. Ca influx through CaV(2.3) VSCCs selectively activates SK channels, revealing the presence of functional Ca microdomains within the spine. Our results suggest that synaptic strength can be modulated by mechanisms that regulate voltage-gated conductances within the spine but do not alter the properties or numbers of synaptic glutamate receptors.     

Unique roles of SK and Kv4.2 potassium channels in dendritic integration

Focal activation of glutamate receptors in distal dendrites of hippocampal pyramidal cells triggers voltage-dependent Ca(2+) channel-mediated plateau potentials that are confined to the stimulated dendrite. We examined the role of dendritic K(+) conductances in determining the amplitude, duration, and spatial compartmentalization of plateau potentials. Manipulations that blocked SK-type Ca(2+)-activated K(+) channels, including apamin and BAPTA dialysis, increased the duration of plateau potentials without affecting their amplitude or compartmentalization. Manipulations that blocked Kv4.2 A-type K(+) channels, including a dominant-negative Kv4.2 construct and 4-aminopyridine, increased the amplitude of plateau potentials by allowing them to recruit neighboring dendrites. Prolongation of plateau potentials or block of Kv4.2 channels at branch points facilitated the ability of dendritic excitation to trigger fast action potentials. SK channels thus underlie repolarization of dendritic plateau potentials, whereas Kv4.2 channels confine these potentials to single dendritic branches, and both act in concert to regulate synaptic integration.     

Network variability limits stimulus-evoked spike timing precision in retinal ganglion cells

Visual, auditory, somatosensory, and olfactory stimuli generate temporally precise patterns of action potentials (spikes). It is unclear, however, how the precision of spike generation relates to the pattern and variability of synaptic input elicited by physiological stimuli. We determined how synaptic conductances evoked by light stimuli that activate the rod bipolar pathway control spike generation in three identified types of mouse retinal ganglion cells (RGCs). The relative amplitude, timing, and impact of excitatory and inhibitory input differed dramatically between On and Off RGCs. Spikes evoked by repeated somatic injection of identical light-evoked synaptic conductances were more temporally precise than those evoked by light. However, the precision of spikes evoked by conductances that varied from trial to trial was similar to that of light-evoked spikes. Thus, the rod bipolar pathway modulates different RGCs via unique combinations of synaptic input, and RGC temporal variability reflects variability in the input this circuit provides.     

Synaptic integration gradients in single cortical pyramidal cell dendrites

Cortical pyramidal neurons receive thousands of synaptic inputs arriving at different dendritic locations with varying degrees of temporal synchrony. It is not known if different locations along single cortical dendrites integrate excitatory inputs in different ways. Here we have used two-photon glutamate uncaging and compartmental modeling to reveal a gradient of nonlinear synaptic integration in basal and apical oblique dendrites of cortical pyramidal neurons. Excitatory inputs to the proximal dendrite sum linearly and require precise temporal coincidence for effective summation, whereas distal inputs are amplified with high gain and integrated over broader time windows. This allows distal inputs to overcome their electrotonic disadvantage, and become surprisingly more effective than proximal inputs at influencing action potential output. Thus, single dendritic branches can already exhibit nonuniform synaptic integration, with the computational strategy shifting from temporal coding to rate coding along the dendrite.     

Action potentials and chemosensitive conductances in the dendrites of olfactory neurons suggest new features for odor transduction

Odors affect the excitability of an olfactory neuron by altering membrane conductances at the ciliated end of a single, long dendrite. One mechanism to increase the sensitivity of olfactory neurons to odorants would be for their dendrites to support action potentials. We show for the first time that isolated olfactory dendrites from the mudpuppy Necturus maculosus contain a high density of voltage-activated Na+ channels and produce Na-dependent action potentials in response to depolarizing current pulses. Furthermore, all required steps in the transduction process beginning with odor detection and culminating with action potential initiation occur in the ciliated dendrite. We have previously shown that odors can modulate Cl- and K+ conductances in intact olfactory neurons, producing both excitation and inhibition. Here we show that both conductances are also present in the isolated, ciliated dendrite near the site of odor binding, that they are modulated by odors, and that they affect neuronal excitability. Voltage- activated Cl- currents blocked by 4,4'-diisothiocyanatostilbene-2,2' disulfonic acid and niflumic acid were found at greater than five times higher average density in the ciliated dendrite than in the soma, whereas voltage-activated K+ currents inhibited by intracellular Cs+ were distributed on average more uniformly throughout the cell. When ciliated, chemosensitive dendrites were stimulated with the odorant taurine, the responses were similar to those seen in intact cells: Cl- currents were increased in some dendrites, whereas in others Cl- or K+ currents were decreased, and responses washed out during whole-cell recording. The Cl- equilibrium potential for intact neurons bathed in physiological saline was found to be -45 mV using an on-cell voltage- ramp protocol and delayed application of channel blockers. We postulate that transduction of some odors is caused by second messenger-mediated modulation of the resting membrane conductance (as opposed to a specialized generator conductance) in the cilia or apical region of the dendrite, and show how this could alter the firing frequency of olfactory neurons.     

Integration of subthreshold and suprathreshold excitatory barrages along the somatodendritic axis of pyramidal neurons

Neurons integrate inputs arriving in different cellular compartments to produce action potentials that are transmitted to other neurons. Because of the voltage- and time-dependent conductances in the dendrites and soma, summation of synaptic inputs is complex. To examine summation of membrane potentials and firing rates, we performed whole-cell recordings from layer 5 cortical pyramidal neurons in acute slices of the rat's somatosensory cortex. We delivered subthreshold and suprathreshold stimuli at the soma and several sites on the apical dendrite, and injected inputs that mimic synaptic barrages at individual or distributed sites. We found that summation of subthreshold potentials differed from that of firing rates. Subthreshold summation was linear when barrages were small but became supralinear as barrages increased. When neurons were discharging repetitively the rules were more diverse. At the soma and proximal apical dendrite summation of the evoked firing rates was predominantly sublinear whereas in the distal dendrite summation ranged from supralinear to sublinear. In addition, the integration of inputs delivered at a single location differed from that of distributed inputs only for suprathreshold responses. These results indicate that convergent inputs onto the apical dendrite and soma do not simply summate linearly, as suggested previously, and that distinct presynaptic afferents that target specific sites on the dendritic tree may perform unique sets of computations.     

Differential roles of Rap1 and Rap2 small GTPases in neurite retraction and synapse elimination in hippocampal spiny neurons

The Rap family of small GTPases is implicated in the mechanisms of synaptic plasticity, particularly synaptic depression. Here we studied the role of Rap in neuronal morphogenesis and synaptic transmission in cultured neurons. Constitutively active Rap2 expressed in hippocampal pyramidal neurons caused decreased length and complexity of both axonal and dendritic branches. In addition, Rap2 caused loss of dendritic spines and spiny synapses, and an increase in filopodia-like protrusions and shaft synapses. These Rap2 morphological effects were absent in aspiny interneurons. In contrast, constitutively active Rap1 had no significant effect on axon or dendrite morphology. Dominant-negative Rap mutants increased dendrite length, indicating that endogenous Rap restrains dendritic outgrowth. The amplitude and frequency of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-mediated miniature excitatory postsynaptic currents (mEPSCs) decreased in hippocampal neurons transfected with active Rap1 or Rap2, associated with reduced surface and total levels of AMPA receptor subunit GluR2. Finally, increasing synaptic activity with GABA(A) receptor antagonists counteracted Rap2's inhibitory effect on dendrite growth, and masked the effects of Rap1 and Rap2 on AMPA-mediated mEPSCs. Rap1 and Rap2 thus have overlapping but distinct actions that potentially link the inhibition of synaptic transmission with the retraction of axons and dendrites.