Changes in apical dendritic structure correlate with sustained ERK1/2 phosphorylation in medial prefrontal cortex of a rat model of dopamine D1 receptor agonist sensitization

Rats lesioned with 6-hydroxydopamine (6-OHDA) as neonates exhibit behavioral and neurochemical abnormalities in adulthood that mimic Lesch-Nyhan disease, schizophrenia, and other developmental disorders of frontostriatal circuit dysfunction. In these animals a latent sensitivity to D1 agonists is maximally exposed by repeated administration of dopamine agonists in the postpubertal period (D1 priming). In neonate-lesioned, adult rats primed with SKF-38393, we found selective, persistent alterations in the morphology of pyramidal neuron apical dendrites in the prelimbic area of the medial prefrontal cortex (mPFC). In these animals, dendrite bundling patterns and the typically straight trajectories of primary dendritic shafts were disrupted, whereas the diameter of higher-order oblique branches was increased. Although not present in neonate-lesioned rats treated with saline, these morphological changes persisted at least 21 days after repeated dosing with SKF-38393, and were not accompanied by markers of neurodegenerative change. A sustained increase in phospho-ERK immunoreactivity in wavy dendritic shafts over the same period suggested a relationship between prolonged ERK phosphorylation and dendritic remodeling in D1-primed rats. In support of this hypothesis, pretreatment with the MEK1/2-ERK1/2 pathway inhibitors PD98059 or SL327, prior to each priming dose of SKF-38393, prevented the morphological changes associated with D1 priming. Together, these findings demonstrate that repeated stimulation of D1 receptors in adulthood interacts with the developmental loss of dopamine to profoundly and persistently modify neuronal signaling and dendrite morphology in the mature prefrontal cortex. Furthermore, sustained elevation of ERK activity in mPFC pyramidal neurons may play a role in guiding these morphological changes in vivo.     

Morphological differences between wild-type and transgenic superoxide dismutase 1 lumbar motoneurons in postnatal mice

Quantitative analysis of the dendritic arborizations of wild-type (WT) and superoxide dismutase 1 (SOD1) postnatal mouse motoneurons was performed following intracellular staining and 3D reconstructions with Neurolucida system. The population of lumbar motoneurons was targeted in the caudal part of the L5 segment, and all labeled motoneurons were located within the same ventrolateral pool. Despite the similar size of the soma and the mean diameter of primary dendrites, the dendritic arborizations of the WT and SOD1 motoneurons showed significant differences in terms of their morphometric parameters. The metric and topological parameters of dendrites show that the total dendritic length and surface area and total number of segments, branching nodes, and tips per motoneuron were significantly higher in SOD1 motoneurons. Our main finding concerns a proliferation of dendritic branches starting at about 100 microm from the soma in the SOD1 motoneurons. However, the longest and mean dendritic paths from soma to terminations were similar, giving a comparable envelope of the dendritic fields. Indeed, the SOD1 motoneurons were larger as a result of abnormal branching. The results suggest that a defect in pruning mechanisms occurs during this developmental period. The abnormal growth of the dendritic arborizations and the reduced excitability of postnatal SOD1 motoneurons could be a neuroprotective response and would represent an early compensatory mechanism against the activity-induced toxicity.     

Heterogeneity in low voltage-activated Ca2+ channel-evoked Ca2+ responses within neurons of the thalamic paraventricular nucleus

Low voltage-activated Ca2+ channels (LVA or T-type Ca2+ channels) are crucial to burst firing and oscillations in thalamocortical relay cells and are exhibited by neurons in the paraventricular nucleus of thalamus (PVT), a dorsal midline nucleus deemed important in the neural representation of motivational behaviours. We used a functional approach (whole-cell patch-clamp electrophysiology combined with confocal laser scanning microscopy) to analyse the spatial distribution of LVA Ca2+ channel-evoked Ca2+ transients in PVT neurons. We observed that the magnitude of LVA Ca2+ channel-evoked Ca2+ transients was significantly greater in proximal dendrites (located up to 20 microm from the soma) than in the soma. In addition, the magnitudes of these Ca2+ transients varied significantly not only among different dendrites of the same cell but also within individual dendrites. These findings suggest that LVA Ca2+ channels are expressed (i) predominantly on the proximal dendrites and (ii) heterogeneously within individual dendrites of PVT neurons. The spatial characteristics of dendritic LVA Ca2+ channels in PVT neurons suggest that these channels may regulate burst firing by modulating dendritic afferent inputs.     

Trigeminothalamic barrelette neurons: natural structural side asymmetries and sensory input-dependent plasticity in adult rats

In the rodent trigeminal principal nucleus (Pr5) the barrelette thalamic-projecting neurons relay information from individual whiskers to corresponding contralateral thalamic barreloids. Here we investigated the presence of lateral asymmetries in the dendritic trees of these neurons, and the morphometric changes resulting from input-dependent plasticity in young adult rats. After retrograde labeling with dextran amines from the thalamus, neurons were digitally reconstructed with Neurolucida™, and metrically and topologically analyzed with NeuroExplorer™. The most unexpected and remarkable result was the observation of side-to-side asymmetries in the barrelette neurons of control rats. These asymmetries more significantly involved the number of low-grade trees and the total dendritic length, which were greater on the left side. Chronic global input loss resulting from infraorbital nerve (IoN) transection, or loss of active touch resulting from whisker clipping in the right neutralized, or even reversed, the observed lateral differences. While results after IoN transection have to be interpreted in the context of partial neuron death in this model, profound bilateral changes were found after haptic loss, which is achieved without inflicting any nerve damage. After whisker trimming, neurons on the left side closely resembled neurons on the right in controls, the natural dendritic length asymmetry being reversed mainly by a shortening of the left trees and a more moderate elongation of the right trees. These results demonstrate that dendritic morphometry is both side- and input-dependent, and that unilateral manipulation of the sensory periphery leads to bilateral morphometric changes in second order neurons of the whisker-barrel system. The presence of anatomical asymmetries in neural structures involved in early stages of somatosensory processing could help explain the expression of sensory input-dependent behavioral asymmetries.     

Distinct properties of two major excitatory inputs to hippocampal pyramidal cells: a computational study

The two main sources of excitatory input to CA1 pyramidal cells, the Schaffer collaterals (SC) and the perforant path (PP), target different regions of the dendritic tree. This spatial segregation may have important consequences for the way in which different inputs affect the activity of principal neurons. We constructed detailed biophysical models of CA1 pyramidal cells, incorporating a variety of active conductances, and investigated the ability of synapses located in different dendritic segments to elicit a somatic voltage response. Synaptic efficacy as seen by the soma was strongly dependent on the site of the synapse, with PP inputs being more severely attenuated than SC inputs. Variability within SC inputs, but not between SC inputs and PP inputs, could be eliminated by appropriate scaling of synaptic efficacy. The spatial and temporal summation of multiple synaptic inputs was also investigated. While summation of SC inputs was linear up to the somatic spike threshold, PP inputs summed in a strongly sublinear fashion, with the somatic response remaining subthreshold even following the simultaneous activation of a large number of synapses and during stimulation with high-frequency trains. Finally, the relative impact of different pathways on somatic activity could be effectively altered by modulating the kinetic properties of dendritic transient K+ channels, corresponding to the activation of ascending modulatory neurotransmitter systems. In this case, the efficacy of the PP was enhanced by the dendritic generation and limited spread of action potentials. Strong PP activation could also evoke dendritic Ca++ spikes, which often triggered a somatic burst.     

Putting neurons in the right places: local interactions in the genesis of retinal architecture

Development of the nervous system can be schematically summarized as (1) making the necessary cells, (2) putting these cells in the right places, and then (3) connecting them appropriately. Each of these steps represents an enormous challenge to our understanding. Focusing on the vertebrate retina, I will consider the question of what defines the right place for a neuron to go. I will illustrate data pointing to the prominent role played by short-range cellular interactions, possibly coordinated by global factors, and will discuss how a few sets of local rules could control cell positioning and proper wiring in retinal circuits.     

Cholinergic Modulation of Neuron Spike Responses to Dendritic and Somatic Application of Excitatory Amino Acids

The effects of acetylcholine on the spike discharges of neurons induced by iontophoretic application of excitatory amino acids to the bodies and dendrites of cells were studied in 98 neurons in living slices of guinea pig parietal cortex. Acetylcholine applied microiontophoretically to both the bodies and dendrites facilitated improvements in the parameters of responses induced by dendritic activation, with significant decreases in latent periods and increases in the intensity and duration of responses. Thee effects were stably induced at distances of 300 m from the body and lasted 1 min after exposure to acetylcholine ended. Responses induced by application of excitatory amino acids directly to the cell body did not change significantly in the presence of acetylcholine regardless of the point on the membrane at which they were applied. It is concluded that the predominant effect of acetylcholine is on the efficiency of dendrosomatic conduction.     

Lateral entorhinal,perirhinal, and amygdala-entorhinal transition projections to hippocampal CA1 and dentate gyrus in the rat: A current source density study

In urethane-anesthetized rats, cortical regions which provide distal dendritic excitation of the dentate gyrus and CA1 of the dorsal hippocampus were studied using current source density analysis. Electrical stimulation of the lateral perforant path (LPP) in the lateral angular bundle, lateral entorhinal cortex (LEC), and amygdala-entorhinal transition (TR) resulted in a current sink in the outer molecular layer of the dentate gyrus accompanied by proximal sources; this sink-source pattern is distinctly different from the source-sink-source pattern evoked by medial perforant path stimulation. The progressive decrease of the sink latency following stimulation of the TR, LEC, and LPP (11.6, 7.8, and 3.6 ms, respectively, at the dorsal blade of the dentate gyrus) suggests a possible sequence of orthodromic activation of these structures. Stimulation of the LEC or TR (collectively termed cortical stimulation) differed from LPP (fiber) stimulation. A low threshold and small chronaxie were characteristic of fiber rather than cortical stimulation. In addition, cortical stimulation, possibly through excitation of intracortical circuits, evoked larger paired-pulse facilitation of the excitatory postsynaptic currents in dentate gyrus and more symmetric excitation of the dorsal and ventral blades of the dentate gyrus as compared to fiber stimulation. Stimulation of the perirhinal cortex (PRh) evoked a short-latency sink in the outer molecular layer of the dentate gyrus with no paired-pulse facilitation, similar to fiber stimulation. A distal dendritic CA1 sink was observed after LPP but not after PRh stimulation. An ibotenic acid injection that lesioned almost all the cells in the perirhinal cortex confirmed the hypothesis that PRh stimulation activated fibers of passage, perhaps in the rostral ventrolateral angular bundle. We conclude that the PRh does not provide a significant excitatory input to the DG or CA1. We have found distinct dendritic excitation of the dentate gyrus by the lateral versus medial perforant paths, and by fiber (LPP and MPP) versus cortical (LEC and TR) stimulation. We also emphasize that processing in the entorhinal cortex is important in the temporal shaping of the signals afferent to the hippocampus. Hippocampus 1997;7:643–655. © 1997 Wiley-Liss, Inc.     

Quantitative analyses of anatomical and electrotonic structures of crayfish nonspiking interneurons by three-dimensional morphometry

The three-dimensional structure of premotor nonspiking interneurons in the terminal abdominal ganglion of crayfish have been studied quantitatively by using a confocal laser-scanning microscope. Their passive membrane properties have also been studied electrophysiologically to analyze their electrotonic structure. In either one of the two major morphological types, anterolateral (AL) and posterolateral (PL), that are characterized by different locations of cell bodies in the ganglion, the monopolar cell body is connected with a fine primary process to a thick main segment projecting numerous fine secondary processes. These two types of cells share a common dendritic field in the neuropil, showing similar anatomical characteristics of dendrites. Electrotonic analyses based on the present anatomical and physiological measurements have revealed that the steady-state voltage-attenuation factors for the secondary processes were not statistically different between the AL- and PL-type cells. Comparison between the premotor nonspiking interneurons and an identified sensory nonspiking interneuron, which was studied previously, has revealed that voltage attenuation over secondary processes in both the centripetal and the centrifugal directions was significantly greater in the sensory than in the premotor interneurons, although the anatomical length of each secondary process from its terminal to the main segment was not different between them. Differences in the electrotonic structure between sensory and premotor nonspiking interneurons indicate their different modes of synaptic integration in the control of postsynaptic nerve cells. J. Comp. Neurol. 392:373–389, 1998. © 1998 Wiley-Liss, Inc.     

Dendritic morphology and its effects on the amplitude and rise-time of synaptic signals in hippocampal CA3 pyramidal cells

Detailed anatomical analysis and compartmental modeling techniques were used to study the impact of CA3b pyramidal cell dendritic morphology and hippocampal anatomy on the amplitude and time course of dendritic synaptic signals. We have used computer-aided tracing methods to obtain accurate three-dimensional representations of 8 CA3b pyramidal cells. The average total dendritic length was 6,332 ± 1,029 μm and 5,062 ± 1,397 μm for the apical and basilar arbors, respectively. These cells also exhibited a rough symmetry in their maximal transverse and septotemporal extents (311 ± 84 μm and 269 ± 106 μm). From the calculated volume of influence (the volume of the neuropil from which the dendritic structures can receive input), it was found that these cells show a limited symmetry between their proximal apical and basilar dendrites (2.1 ± 1.2 × 10⁶ μm³ and 3.5 ± 1.1 × 10⁶ μm³, respectively). Based upon these data, we propose that the geometry of these cells can be approximated by a combination of two cones for the apical arbor and a single cone for the basilar arbor. The reconstructed cells were used to build compartmental models and investigate the extent to which the cellular anatomy determines the efficiency with which dendritic synaptic signals are transferred to the soma. We found that slow, long lasting signals show only approximately a 50% attenuation when they occur in the most distal apical dendrites. However, synaptic transients similar to those seen in fast glutamatergic transmission are transferred much less efficiently, showing up to a 95% attenuation. The relationship between the distance along the dendrites and the observed attenuation for a transient is described simply by single exponential functions with parameters of 195 and 147 μm for the apical and basilar arbors respectively. In contrast, there is no simple relation that describes how a transient is attenuated with respect to these cells' stratified inputs. This lack of a simple relationship arises from the radial orientation of the proximal apical and basilar dendrites. When combined, the anatomical and modeling data suggest that a CA3b cell can be approximated in three dimensions as the combination of three cones. The amplitude and time-course for a synaptic transient can then be predicted using two simple equations. © 1996 Wiley-Liss, Inc.