Increased proximal bifurcation of CA1 pyramidal apical dendrites in sema3A mutant mice

Semaphorin‐3A (Sema3A) is an attractive guidance molecule for cortical apical dendrites. To elucidate the role of Sema3A in hippocampal dendritic formation, we examined the Sema3A expression pattern in the perinatal hippocampal formation and analyzed hippocampal dendrites of the brains from young adult sema3A mutant mice. Sema3A protein was predominantly expressed in the hippocampal plate and the inner marginal zone at the initial period of apical dendritic growth. Neuropilin‐1 and plexin‐A, the receptor components for Sema3A, were also localized in the same regions. The Golgi impregnation method revealed that in wildtype mice more than 90% of hippocampal CA1 pyramidal neurons extended a single trunk or apical trunks bifurcated in stratum radiatum. Seven percent of the pyramidal neurons showed proximal bifurcation of apical trunks in stratum pyramidale or at the border of the stratum pyramidale and stratum radiatum. In sema3A mutant mice, proximally bifurcated apical dendrites were increased to 32%, while the single apical dendritic pyramidal neurons were decreased. We designate this phenotype in sema3A mutant mice as “proximal bifurcation.” In the dissociated culture system, approximately half of the hippocampal neurons from wildtype mice resembled pyramidal neurons, which possess a long, thick, and tapered dendrite. In contrast, only 30% of the neurons from sema3A mutants exhibited pyramidal‐like morphology. Proximal bifurcation of CA1 pyramidal neurons was also increased in the mutant mice of p35, an activator of cyclin‐dependent kinase 5 (Cdk5). Thus, Sema3A may facilitate the initial growth of CA1 apical dendrites via the activation of p35/Cdk5, which may in turn signal hippocampal development. J. Comp. Neurol. 516:360–375, 2009. © 2009 Wiley‐Liss, Inc.     

Blockade of insulin‐like growth factor‐I has complex effects on structural plasticity in the hippocampus

Physical exercise enhances adult neurogenesis in the hippocampus. Running induces the uptake of blood insulin‐like growth factor‐I (IGF‐I) into the brain. A causal link between these two phenomena has been reported; running‐induced increases in adult neurogenesis can be blocked by peripheral infusion of anti‐IGF‐I. Running also alters other aspects of hippocampal structure, including dendritic spine density. It remains unclear, however, whether these effects are also mediated through an IGF‐I mechanism. To examine this possibility, we blocked peripheral IGF‐I and examined adult neurogenesis and dendritic spine density in treadmill running mice. Two weeks of running resulted in an increase in cell proliferation in the dentate gyrus (DG) as well as an increase in dendritic spine density on DG granule cells and basal dendrites of CA1 pyramidal neurons, while having no effect on apical or basal dendritic spine density of CA3 pyramidal neurons. IGF‐I blockade reduced cell proliferation in both sedentary and running mice, but by contrast, this treatment had no effect on granule cell or CA3 pyramidal cell dendritic spine density in sedentary or running mice. However, IGF‐I antibody treatment seemed to prevent the running‐induced increase in spine density on basal dendrites of CA1 pyramidal cells. These results suggest that IGF‐I exerts a complex influence over hippocampal structure and that its effects are not restricted to those induced by running. © 2009 Wiley‐Liss, Inc.     

Changes in BDNF-immunoreactive structures in the hippocampal formation of the aged macaque monkey.

We investigated the changes of brain-derived neurotrophic factor (BDNF)-immunoreactive structures in the hippocampal formation of aged macaques (Macaca fuscata fuscata). At adult stages (10 and 12 years), BDNF immunoreactivity occurred in the neurons of the dentate gyrus, the pyramidal neurons in the CA1, CA2, CA3 subfields and the subiculum, and the neurons in the CA4 subfield and the entorhinal cortex. The apical dendrites were also BDNF immunopositive. In aged monkeys (26, 30 and 32 years), the intensity of the BDNF-immunoreactivity declined significantly in cell bodies and dendrites of the neurons in the hippocampal formation except the CA2 pyramidal neurons. These findings indicate that BDNF is one of the vulnerable signal molecules during the aging process of the primate hippocampal formation.     

Early life stress followed by subsequent adult chronic stress potentiates anxiety and blunts hippocampal structural remodeling

Early life stress produces long‐term alterations in cognition, emotionality, and stress responsiveness. The stress‐sensitive hippocampal formation plays a role in producing many of these alterations. We report that adult male rats exposed to early life stress, in the form of maternal separation (MS), exhibit baseline impairment of hippocampal dependent memory and following three weeks of chronic restraint stress (CRS) exhibit heightened anxiety‐like behavior and alterations in the morphology of hippocampal CA3 pyramidal neurons. Specifically, as measured by the object placement task, MS offspring demonstrated impaired spatial memory compared with nonmaternally separated rats (NMS). Moreover, compared with NMS rats, subsequent CRS exposure of MS rats increased novelty‐induced corticosterone secretion and potentiated anxiety‐like behavior as measured by the elevated plus maze. Further, CRS exposed MS rats did not exhibit shortening of apical dendritic length compared with nonstressed MS rats, whereas CRS exposed NMS rats did show significant dendritic shrinkage compared with nonstressed NMS rats. The blunted CRS‐induced remodeling of apical dendritic length in MS rats is likely due to a baseline deficiency in dendritic length; MS rats exhibit a trend towards shorter apical dendrites in comparison to NMS rats. CRS exposure in both MS and NMS rats, however, induced a reduction in apical dendritic branching. Finally, there was a significant correlation between apical dendritic length and novelty‐induced corticosterone level, while there was not a significant correlation with anxiety‐like behavior. Overall, our results suggest preserved but blunted hippocampal structural plasticity in MS rats that is not sufficient to compensate for hippocampal dysfunction and hypersensitivity to CRS. © 2010 Wiley Periodicals, Inc., Inc.     

Carboxypeptidase E knockout mice exhibit abnormal dendritic arborization and spine morphology in central nervous system neurons

Carboxypeptidase E (CPE) is involved in maturation of neuropeptides and sorting of brain‐derived neurotrophic factor (BDNF) to the regulated pathway for activity‐dependent secretion from CNS neurons. CPE knockout (CPE‐KO) mice have many neurological deficits, including deficits in learning and memory. Here, we analyzed the dendritic arborization and spine morphology of CPE‐KO mice to determine a possible correlation of defects in such structures with the neurological deficits observed in these animals. Analysis of pyramidal neurons in layer V of cerebral cortex and in hippocampal CA1 region in 14‐week‐old CPE‐KO mice showed more dendritic complexity compared with wild type (WT) mice. There were more dendritic intersections and more branch points in CPE‐KO vs. WT neurons. Comparison of pyramidal cortical neurons in 6‐ vs. 14‐week‐old WT mice showed a decrease in dendritic arborization, reflecting the occurrence of normal dendritic pruning. However, this did not occur in CPE‐KO neurons. Furthermore, analysis of spine morphology demonstrated a significant increase in the number of D‐type spines regarded as nonfunctional in the cortical neurons of CPE‐KO animals. Our findings suggest that CPE is an important, novel player in mediating appropriate dendritic patterning and spine formation in CNS neurons. © 2009 Wiley‐Liss, Inc.     

Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca2+‐permeable TRPC6 channels

The standardized extract of the St. John's wort plant (Hypericum perforatum ) is commonly used to treat mild to moderate depression. Its active constituent is hyperforin, a phloroglucinol derivative that reduces the reuptake of serotonin and norepinephrine by increasing intracellular Na⁺ concentration through the activation of nonselective cationic TRPC6 channels. TRPC6 channels are also Ca²⁺‐permeable, resulting in intracellular Ca²⁺ elevations. Indeed, hyperforin activates TRPC6‐mediated currents and Ca²⁺ transients in rat PC12 cells, which induce their differentiation, mimicking the neurotrophic effect of nerve growth factor. Here, we show that hyperforin modulates dendritic spine morphology in CA1 and CA3 pyramidal neurons of hippocampal slice cultures through the activation of TRPC6 channels. Hyperforin also evoked intracellular Ca²⁺ transients and depolarizing inward currents sensitive to the TRPC channel blocker La³⁺, thus resembling the actions of the neurotrophin brain‐derived neurotrophic factor (BDNF) in hippocampal pyramidal neurons. These results suggest that the antidepressant actions of St. John's wort are mediated by a mechanism similar to that engaged by BDNF. © 2012 Wiley Periodicals, Inc.     

Blockade of BDNF signaling turns chemically‐induced long‐term potentiation into long‐term depression

Long‐term potentiation (LTP) is accompanied by increased spine density and dimensions triggered by signaling cascades involving activation of the neurotrophin brain‐derived neurotrophic factor (BDNF) and cytoskeleton remodeling. Chemically‐induced long‐term potentiation (c‐LTP) is a widely used cellular model of plasticity, whose effects on spines have been poorly investigated. We induced c‐LTP by bath‐application of the N‐methyl‐d ‐aspartate receptor (NMDAR) coagonist glycine or by the K⁺ channel blocker tetraethylammonium (TEA) chloride in cultured hippocampal neurons and compared the changes in dendritic spines induced by the two models of c‐LTP and determined if they depend on BDNF/TrkB signaling. We found that both TEA and glycine induced a significant increase in stubby spine density in primary and secondary apical dendrites, whereas a specific increase in mushroom spine density was observed upon TEA application only in primary dendrites. Both TEA and glycine increased BDNF levels and the blockade of tropomyosin‐receptor‐kinase receptors (TrkRs) by the nonselective tyrosine kinase inhibitor K‐252a or the selective allosteric TrkB receptor (TrkBR) inhibitor ANA‐12, abolished the c‐LTP‐induced increase in spine density. Surprisingly, a blockade of TrkBRs did not change basal spontaneous glutamatergic transmission but completely changed the synaptic plasticity induced by c‐LTP, provoking a shift from a long‐term increase to a long‐term depression (LTD) in miniature excitatory postsynaptic current (mEPSC) frequency. In conclusion, these results suggest that BDNF/TrkB signaling is necessary for c‐LTP‐induced plasticity in hippocampal neurons and its blockade leads to a switch of c‐LTP into chemical‐LTD (c‐LTD). © 2013 Wiley Periodicals, Inc.     

Architectural changes to CA1 pyramidal neurons in adult and aged mice after peripheral immune stimulation

The expression of several inflammatory cytokines that inhibit synaptic plasticity and hippocampal-dependent learning and memory is higher in the brains of aged mice compared to young adults after peripheral injection of lipopolysaccharide (LPS). In this study we investigated whether the exaggerated inflammatory cytokine response in the hippocampus of aged mice after IP injection of LPS is associated with architectural changes to dendrites of pyramidal neurons in the dorsal CA1 hippocampus. Compared to young adults, aged mice had higher basal expression of MHC class II, lower basal expression of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), and a decrease in total dendritic length in both the basal and apical tree. After IP LPS administration, expression of IL-1β, IL-6, and TNFα mRNA was higher in hippocampus of aged mice compared to young adults whereas NGF and BDNF mRNA was reduced similarly in both age groups. The basal dendritic tree was not affected by LPS in either adult or aged mice 72 h after treatment; however, length and branching of the apical tree was reduced by LPS in aged but not adult mice. The present findings indicate that a peripheral infection in the aged can cause a heightened inflammatory cytokine response in the hippocampus and atrophy of hippocampal neurons. Architectural changes to dorsal CA1 hippocampal neurons may contribute to cognitive disorders evident in elderly patients with an infection.     

Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: a paradox

Repeated stress induces atrophy, or remodeling, of apical dendrites in hippocampal CA3 pyramidal neurons. In rats, the stress effect is blocked by adrenal steroid synthesis inhibitors, and mimicked by daily injection of corticosterone. We report that non-invasive administration of corticosterone in the drinking water (400 μg/ml) also produced atrophy of apical dendrites in CA3. Unexpectedly, the combination of daily stress and oral corticosterone negated the effects of either treatment alone, and no changes in the apical dendritic length or branching pattern of CA3 pyramidal neurons were observed compared to control unstressed rats.     

Temporal manipulation of transferrin‐receptor‐1‐dependent iron uptake identifies a sensitive period in mouse hippocampal neurodevelopment

Iron is a necessary substrate for neuronal function throughout the lifespan, but particularly during development. Early life iron deficiency (ID) in humans (late gestation through 2–3 yr) results in persistent cognitive and behavioral abnormalities despite iron repletion. Animal models of early life ID generated using maternal dietary iron restriction also demonstrate persistent learning and memory deficits, suggesting a critical requirement for iron during hippocampal development. Precise definition of the temporal window for this requirement has been elusive due to anemia and total body and brain ID inherent to previous dietary restriction models. To circumvent these confounds, we developed transgenic mice that express tetracycline transactivator regulated, dominant negative transferrin receptor (DNTfR1) in hippocampal neurons, disrupting TfR1 mediated iron uptake specifically in CA1 pyramidal neurons. Normal iron status was restored by doxycycline administration. We manipulated the duration of ID using this inducible model to examine long‐term effects of early ID on Morris water maze learning, CA1 apical dendrite structure, and defining factors of critical periods including parvalbmin (PV) expression, perineuronal nets (PNN), and brain‐derived neurotrophic factor (BDNF) expression. Ongoing ID impaired spatial memory and resulted in disorganized apical dendrite structure accompanied by altered PV and PNN expression and reduced BDNF levels. Iron repletion at P21, near the end of hippocampal dendritogenesis, restored spatial memory, dendrite structure, and critical period markers in adult mice. However, mice that remained hippocampally iron deficient until P42 continued to have spatial memory deficits, impaired CA1 apical dendrite structure, and persistent alterations in PV and PNN expression and reduced BDNF despite iron repletion. Together, these findings demonstrate that hippocampal iron availability is necessary between P21 and P42 for development of normal spatial learning and memory, and that these effects may reflect disruption of critical period closure by early life ID. © 2012 Wiley Periodicals, Inc.     

Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity

α‐Thalassemia X‐linked intellectual disability (ATR‐X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2‐type chromatin‐remodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX‐cKO) causes deficits in long‐term hippocampus‐dependent spatial memory. Thus, we hypothesized that ATRX‐cKO mice will display impaired hippocampal synaptic transmission and plasticity. In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane‐anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including paired‐pulse facilitation (PPF) at 50‐ms interpulse interval, and by their long‐term potentiation (LTP) induced by theta‐frequency burst stimulation. Baseline single‐pulse excitatory response at each synapse did not differ between ATRX‐cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX‐cKO mice. While basal dendritic LTP of the first‐pulse excitatory response was not affected in ATRX‐cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long‐term spatial memory deficits in ATRX‐cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR‐X syndrome patients.     

Constitutive Ras activity induces hippocampal hypertrophy and remodeling of pyramidal neurons in synRas mice

The small G protein Ras, which is involved critically in neurotrophic signal transduction, has been implicated in neuronal plasticity of both the developing and the adult nervous systems. In the present study, the cumulative effects of constitutive Ras activity from early in postnatal development into the adult upon the morphology of hippocampal pyramidal neurons were investigated in synRas mice overexpressing Val12-Ha-Ras postmitotically under the control of the rat synapsin I promoter. In synRas mice, stereologic investigations revealed hypertrophy of the hippocampus associated with an increase in perikaryal size of pyramidal neurons within the CA2/CA3 region and the gyrus dentatus. Morphometric analyses of Lucifer Yellow-filled CA1 pyramidal neurons, in addition, demonstrated considerable expansion of dendritic arbors. The increase in basal dendritic size was caused primarily by alterations of intermediate and distal segments and was associated with an enlarged dendritic surface. Apical dendrites showed similar but more moderate changes, which were attributed mainly to elongation of terminal segments. Sholl analyses illustrated higher complexity of both basal and apical trees. Despite significant morphologic alterations, dendritic arbors preserve their major design principles. The synaptic density within the stratum radiatum of CA1 remained unchanged; however, increases in the total hippocampal volume and in apical dendritic size imply an increment in the absolute number of synaptic contacts. The data presented here suggest a critical involvement of Ras dependent signaling in morphoregulatory processes during the maturation and in the maintenance of hippocampal pyramidal neurons.     

BDNF enhances dendritic Ca2+ signals evoked by coincident EPSPs and back-propagating action potentials in CA1 pyramidal neurons

BDNF, a member of the neurotrophin family, is emerging as a key modulator of synaptic structure and function in the CNS. Due to the critical role of postsynaptic Ca(2+) signals in dendritic development and synaptic plasticity, we tested whether long-term exposure to BDNF affects Ca(2+) elevations evoked by coincident excitatory postsynaptic potentials (EPSPs) and back-propagating action potentials (bAPs) in spiny dendrites of CA1 pyramidal neurons within hippocampal slice cultures. In control neurons, a train of 5 coincident EPSPs and bAPs evoked Ca(2+) elevations in oblique radial branches of the main apical dendrite that were of similar amplitude than those evoked by a train of 5 bAPs alone. On the other hand, dendritic Ca(2+) signals evoked by coincident EPSPs and bAPs were always larger than those triggered by bAPs in CA1 neurons exposed to BDNF for 48 h. This difference was not observed after blockade of NMDA receptors (NMDARs) with D,L-APV, but only in BDNF-treated neurons, suggesting that Ca(2+) signals in oblique radial dendrites include a synaptic NMDAR-dependent component. Co-treatment with the receptor tyrosine kinase inhibitor k-252a prevented the effect of BDNF on coincident dendritic Ca(2+) signals, suggesting the involvement of neurotrophin Trk receptors. These results indicate that long-term exposure to BDNF enhances Ca(2+) signaling during coincident pre- and postsynaptic activity in small spiny dendrites of CA1 pyramidal neurons, representing a potential functional consequence of neurotrophin-mediated dendritic remodeling in developing neurons.     

The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF^+/?). We show that whereas early‐LTD (<90min) requires BDNF, short‐term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF^+/? mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF^+/? mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus‐dependent memory. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Serotonin transporter knockout and repeated social defeat stress: impact on neuronal morphology and plasticity in limbic brain areas

Low expression of the human serotonin transporter (5-HTT) gene presumably interacts with stressful life events enhancing susceptibility for affective disorders. 5-Htt knockout (KO) mice display an anxious phenotype, and behavioural differences compared to wild-type (WT) mice are exacerbated after repeated loser experience in a resident-intruder stress paradigm. To assess whether genotype-dependent and stress-induced behavioural differences are reflected in alterations of neuronal morphology in limbic areas, we studied dendritic length and complexity of pyramidal neurons in the anterior cingulate and infralimbic cortices (CG, IL), hippocampus CA1 region, and of pyramidal neurons and interneurons in the lateral (La) and basolateral (BL) amygdaloid nuclei in Golgi-Cox-stained brains of male WT and 5-Htt KO control and loser mice. Spine density was analysed for IL apical and amygdaloid apical and basal pyramidal neuron dendrites. While group differences were absent for parameters analysed in CG, CA1 and amygdaloid interneurons, pyramidal neurons in the IL displayed tendencies to shorter and less spinous distal apical dendrites in 5-Htt KO controls, and to extended proximal dendrites in WT losers compared to WT controls. In contrast, spine density of several dendritic compartments of amygdaloid pyramids was significantly higher in 5-Htt KO mice compared to WT controls. While a tendency to increased spine density was observed in the same dendritic compartments in WT after stress, changes were lacking in stressed compared to control 5-Htt KO mice. Our findings indicate that disturbed 5-HT homeostasis results in alterations of limbic neuronal morphology, especially in higher spinogenesis in amygdaloid pyramidal neurons. Social stress leads to similar but less pronounced changes in the WT, and neuroplasticity upon stress is reduced in 5-Htt KO mice.     

Peritoneal implantation of macroencapsulated porcine pancreatic islets in diabetic rats ameliorates severe hyperglycemia and prevents retraction and simplification of hippocampal dendrites

The hippocampus of rats with uncontrolled insulin-dependent diabetes undergoes retraction and simplification of apical dendrites of the CA3 pyramidal neurons and synaptic rearrangements within mossy fiber terminals that could alter hippocampal connectivity and function. The intraperitoneal implantation of hydrophilic agarose macrobeads containing porcine islets for 17 days in rats with streptozotocin-induced diabetes results in normalization of body weight gain, significant control of hyperglycemia and prevention of hippocampal dendritic remodeling, and therefore, provides an effective therapeutic option.     

Corticosterone reduces dendritic complexity in developing hippocampal CA1 neurons

Although prolonged stress and corticosteroid exposure induce morphological changes in the hippocampal CA3 area, the adult CA1 area is quite resistant to such changes. Here we addressed the question whether elevated corticosteroid hormone levels change dendritic complexity in young, developing CA1 cells. In organotypic cultures (prepared from P5 rats) that were 14–21 days cultured in vitro, two doses of corticosterone (30 and 100 nM) were tested. Dendritic morphology of CA1 neurons was established by imaging neurons filled with the fluorescent dye Alexa. Application of 100 nM corticosterone for 20 minutes induced atrophy of the apical dendritic tree 1–4 hours later. Fractal analysis showed that total neuronal complexity was reduced twofold when compared with vehicle‐treated neurons. Exposing organotypic slices to 30 nM corticosterone reduced apical length in a more delayed manner: only neurons examined more than 2 hours after exposure to corticosterone showed atrophy of the apical dendritic tree. Neither dose of corticosterone affected the length of basal dendrites or spine density. Corticosterone was ineffective in changing morphology of the apical dendrites when tested in the presence of the glucocorticoid receptor antagonist RU38486. These results suggest that high physiological levels of corticosterone, via activation of the glucocorticoid receptor, can, during the course of only a few hours, reduce the dendritic complexity of CA1 pyramidal neurons in young, developing hippocampal tissue. These findings suggest that it is relevant to maintain plasma corticosterone levels low during hippocampal development. © 2009 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.