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J W Swann

Publications and source records attributed to J W Swann.

At least 19 recordsLinked to original sources
PubMed2005

A role for L-type calcium channels in the maturation of parvalbumin-containing hippocampal interneurons.

While inhibitory interneurons are well recognized to play critical roles in the brain, relatively little is know about the molecular events that regulate their growth and differentiation. Calcium ions are thought to be important in neuronal development and L-type voltage gated Ca(+2) channels have been implicated in activity-dependent mechanisms of early-life. However, few studies have examined the role of these channels in the maturation of interneurons. The studies reported here were conducted in hippocampal slice cultures and indicate that the L-type Ca(+2) channel agonists and antagonists accelerate and suppress respectively the growth of parvalbumin-containing interneurons. The effects of channel blockade were reversible suggesting they are not the result of interneuronal cell death. Results from immunoblotting showed that these drugs have similar effects on the expression of the GABA synthetic enzymes, glutamic acid decarboxylase65, glutamic acid decarboxylase67 and the vesicular GABA transporter. This suggests that L-type Ca(+2) channels regulate not only parvalbumin expression but also interneuron development. These effects are likely mediated by actions on the interneurons themselves since the alpha subunits of L-type channels, voltage-gated calcium channel subunit 1.2 and voltage-gated calcium channel subunit 1.3 were found to be highly expressed in neonatal mouse hippocampus and co-localized with parvalbumin in interneurons. Results also showed that while these interneurons can contain either subunit, voltage-gated calcium channel subunit 1.3 was more widely expressed. Taken together results suggest that an important subset of developing interneurons expresses L-type Ca(+2) channels alpha subunits, voltage-gated calcium channel subunit 1.2 and especially voltage-gated calcium channel subunit 1.3 and that these channels likely regulate the development of these interneurons in an activity-dependent manner.

Animals↗
PubMed2001

GABAergic neurons that pioneer hippocampal area CA1 of the mouse: morphologic features and multiple fates.

Dramatic changes occur in the expression of glutamic acid decarboxylase (GAD67) immunoreactivity in mouse hippocampus during postnatal development. Most striking is the presence of a dense population of immunopositive cells in stratum radiatum and stratum oriens in area CA1 during the first postnatal week. Between days 5 and 10, these cells disappear and the GAD67 immunoreactivity begins to resemble that of adulthood. These neurons are considered pioneer cells, and studies were undertaken to determine their fate. Between days 5 and 50, area CA1 doubles in size; however, the loss of cells expressing GAD67 mRNA cannot be explained solely by dilution resulting from hippocampal growth. In stratum radiatum, cell loss is particularly dramatic. Although between days 5 and 15, many cells seem to migrate from stratum radiatum to its border with stratum lacunosum-moleculare, both fate maps of pioneer cells labeled with bromodeoxyuridine (BrdU) on embryonic day 13 (E13) and in situ DNA end-labeling studies suggest that some cells die by means of programmed cell death. However, not all pioneer cells die, because many cells labeled with BrdU on E13 are present in adulthood and express markers for and have anatomic features of hippocampal interneurons. In conclusion, events that underlie the age-dependent disappearance of gamma-aminobutyric acid (GABA) -ergic pioneer cells are complex and cannot be completely explained by dilution in an expanding neuropile. Although some GABAergic pioneer cells likely undergo programmed cell death during the first postnatal weeks, others relocate within hippocampal laminae and terminally differentiate into the interneurons of adulthood.

Aging↗
PubMed2001

Neuronal activity and the establishment of normal and epileptic circuits during brain development.

The question we attempted to address in this chapter is: Do brief but recurrent seizures in early life alter the ontogeny of hippocampal networks in ways that produce epileptic circuits? Results from the tetanus toxin model suggest that this is likely the case. Following seizures in Postnatal Weeks 2 and 3, most adult rats have a focal epilepsy that arises from hippocampus. Recordings from hippocampal slices support this conclusion since they demonstrated the occurrence of spontaneous network discharges in normal artificial cerebrospinal fluid. Moreover, when GABA-A receptor-mediated synaptic transmission was suppressed, slices from adult epileptic rats produced prolonged electrographic seizures which are never observed in control rats. This suggests that hyperexcitable recurrent excitatory networks contribute to hippocampal seizures in this model. In light of this, anatomical results from biocytin-filled neurons were surprising. Results suggest that recurrent axon arbors neither sprout additional branches as a result of seizure activity nor maintain their exuberant branching patterns of early life. Thus, excessive connectivity cannot explain seizure generation. Axon arbors either remodel in normal ways or prune additional collaterals as a result of ongoing epileptiform discharging. At the same time that axon arbors remodel, the dendrites of these cells have decreased dendritic spine density, suggesting a partial deafferentation. While a complete understanding of the origins of spine loss requires further investigation, we hypothesize that this loss is a product of a partial deafferentation that occurs due to excessive and abnormal selection of synaptic connections. Network-induced heterosynaptic LTD of noncoincidentally active afferants may be one mechanism that leads to a loss of synapses. Moreover, competition among and selection between individual recurrent excitatory synapses may contribute to spine loss as well. The "winners" of this competition, the most potent and effective early-formed recurrent excitatory synapses, are likely key contributors to seizure generation in this model and possibly in humans with early-onset temporal lobe epilepsy.

Aging↗
PubMed2001

Spatial learning deficits without hippocampal neuronal loss in a model of early-onset epilepsy.

Studies were undertaken to examine the effects recurrent early-life seizures have on the ability of rats to acquire spatial memories in adulthood. A minute quantity of tetanus toxin was injected unilaterally into the hippocampus on postnatal day 10. Within 48 h, rats developed recurrent seizures that persisted for 1 week. Between postnatal days 57 and 61, rats were trained in a Morris water maze. Toxin-injected rats were markedly deficient in learning this task. While these rats showed gradual improvement in escape latencies over 20 trials, their performance always lagged behind that of controls. Poor performance could not be explained by motor impairments or motivational difficulties since swimming speed was similar for the groups. Only eight of 16 toxin-injected animals showed focal interictal spikes in the hippocampus during electroencephalographic recordings. This suggests that learning deficiencies and chronic epilepsy may be independent products of recurrent early-life seizures. A quantitative analysis of hippocampus revealed a significant decrease in neuronal density in stratum pyramidale of experimental rats. However, the differences were largely explained by a concomitant increase in the area of stratum pyramidale. Studies of glial fibrillary acidic protein expression and spread of horseradish peroxidase-conjugated tetanus toxin in the hippocampus suggest that the dispersion of cell bodies in stratum pyramidale can neither be explained by a reactive gliosis nor the direct action of the toxin itself. Taken together, we suggest that recurrent seizures beginning in early life can lead to a significant deficiency in spatial learning without ongoing hippocampal synchronized network discharging or a substantial loss of hippocampal pyramidal cells.

Action Potentials↗
PubMed2001

Fluorescence in situ hybridization method for co-localization of mRNA and GEP.

Co-localization studies using green fluorescent protein (GFP) and fluorescence immunohistochemistry have become commonplace. However, co-localization studies using GFP and mRNA in situ hybridization are rare, in large part because typical in situ hybridization reaction conditions often lead to the loss of GFP fluorescence. Here, we describe a new fluorescence mRNA in situ hybridization protocol using cRNA riboprobes that leaves GFP fluorescence intact. This protocol is based on a urea-based hybridization buffer and the Tyramide Signal Amplification system. This protocol should provide researchers engaged in the use of GFP with a solid starting point for adapting their own in situ hybridization protocols.

Animals↗
PubMed2000

Novel hippocampal interneuronal subtypes identified using transgenic mice that express green fluorescent protein in GABAergic interneurons.

The chief inhibitory neurons of the mammalian brain, GABAergic neurons, are comprised of a myriad of diverse neuronal subtypes. To facilitate the study of these neurons, transgenic mice were generated that express enhanced green fluorescent protein (EGFP) in subpopulations of GABAergic neurons. In one of the resulting transgenic lines, called GIN (GFP-expressing Inhibitory Neurons), EGFP was found to be expressed in a subpopulation of somatostatin-containing GABAergic interneurons in the hippocampus and neocortex. In both live and fixed brain preparations from these mice, detailed microanatomical features of EGFP-expressing interneurons were readily observed. In stratum oriens of the hippocampus, EGFP-expressing interneurons were comprised almost exclusively of oriens/alveus interneurons with lacunosum-moleculare axon arborization (O-LM cells). In the neocortex, the somata of EGFP-expressing interneurons were largely restricted to layers II-IV and upper layer V. In hippocampal area CA1, two previously uncharacterized subtypes of interneurons were identified using the GIN mice: stratum pyramidale interneurons with lacunosum-moleculare axon arborization (P-LM cells) and stratum radiatum interneurons with lacunosum-moleculare axon arborization (R-LM cells). These newly identified interneuronal subtypes appeared to be closely related to O-LM cell, as they selectively innervate stratum lacunosum-moleculare. Whole-cell patch-clamp recordings revealed that these cells were fast-spiking and showed virtually no spike frequency accommodation. The microanatomical features of these cells suggest that they function primarily as "input-biasing" neurons, in that synaptic volleys in stratum radiatum would lead to their activation, which in turn would result in selective suppression of excitatory input from the entorhinal cortex onto CA1 pyramidal cells.

Action Potentials↗
PubMed2000

Blockade of neuronal activity during hippocampal development produces a chronic focal epilepsy in the rat.

During brain development, neuronal activity can transform neurons characterized by widely ranging axonal projections to ones with more restricted patterns of synaptic connectivity. Previous studies have shown that an exuberant outgrowth of local recurrent excitatory axons occurs in hippocampal area CA3 during postnatal weeks 2 and 3. Axons are remodeled with maturation, and nearly half of the branches are eliminated. Postnatal weeks 2 and 3 also coincide with a "critical" period of development, when CA3 networks have a marked propensity to generate electrographic seizures. In an attempt to prevent axonal remodeling, local circuit activity was blocked unilaterally in dorsal hippocampus by continuous infusion of tetrodotoxin (TTX). Field potential recordings from behaving animals were dramatically altered when TTX infusion was initiated at the beginning of the critical period, week 2, but not later in life. Spontaneous, synchronized spikes and electrographic seizures with behavioral accompaniments were observed after 4 weeks of TTX infusion and persisted into adulthood. When recordings were made during TTX infusion, synchronized spiking was recorded in ventral hippocampus as early as 2 weeks after infusate introduction. At this same time, extracellular field recordings from in vitro slices demonstrated spontaneous network-driven "mini-bursts" arising from ventral hippocampal slices. These were abolished by glutamate receptor antagonists. Whole-cell recordings from CA3 neurons revealed bursts of excitatory synaptic potentials coincident with the network bursts recorded extracellularly. Thus, local assemblies of mutually excitatory CA3 pyramidal cells are hyperexcitable in these rats. Whether alterations in developmental axonal remodeling mediate these effects awaits further studies.

Animals↗
PubMed2000

Spine loss and other dendritic abnormalities in epilepsy.

Studies of neurons from human epilepsy tissue and comparable animal models of focal epilepsy have consistently reported a marked decrease in dendritic spine density on hippocampal and neocortical pyramidal cells. Spine loss is often accompanied by focal varicose swellings or beading of dendritic segments. An ongoing excitotoxic injury of dendrites (dendrotoxicity), produced by excessive release of glutamate during seizures, is often assumed to produce these abnormalities. Indeed, application of glutamate receptor agonists to dendrites can produce both spine loss and beading. However, the cellular mechanisms underlying the two processes appear to be different. One recent study suggests NMDA-induced spine loss is produced by Ca2+-mediated alterations of the spine cytoskeleton. In contrast, dendritic beading is not dependent on extracellular Ca2+; instead, it appears to be produced by the movement of Na+ and Cl- intracellularly and an obligate movement of water to maintain osmolarity. A decrease in dendritic spine density was recently reported in a model of recurrent focal seizures in early life. Unlike results from other models, dendritic beading was not observed, and other signs of neuronal injury and death were absent. Thus, additional mechanisms to those of excitotoxicity may produce dendritic spine loss in epileptic tissue. A hypothesis is presented that spine loss can be a product of a partial deafferentation of pyramidal cells, resulting from an activity-dependent pruning of neuronal connectivity induced by recurring seizures. The dendritic abnormalities observed in epilepsy are commonly suggested to be a product and not a cause of epilepsy. However, anatomical remodeling may be accompanied by alterations in molecular expression and targeting of both voltage- and ligand-gated channels in dendrites. It is conceivable that such changes could contribute to the neuronal hyperexcitability of epilepsy.

Animals↗
PubMed2000

Cellular abnormalities and synaptic plasticity in seizure disorders of the immature nervous system.

The nervous system has an enhanced capacity to generate seizures during a restricted phase of postnatal development. Studies in animals and particularly in in vitro brain slices from hippocampus and neocortex have been instrumental in furthering an understanding of the underlying processes. Developmental alterations in glutaminergic excitatory synaptic transmission appear to play a key role in the enhanced seizure susceptible of rodents during the second and third week of life. Prior to this period, the number of excitatory synapses is relatively low. The scarcity of connections and the inability of the existing synapses to release glutamate when activated at high frequencies likely contribute importantly to the resistance of neonates to seizures. However, at the beginning of week 2, a dramatic outgrowth of excitatory synapses occurs, and these synapses are able to faithfully follow activation at high frequencies. These changes, coupled with the prolonged nature of synaptic potentials in early life, likely contribute to the ease of seizure generation. After this time, seizure susceptibility declines, patterns of local synaptic connectivity remodel, and some synapses are pruned. Concurrently, the duration of excitatory postsynaptic potentials shortens due at least in part to a switch in the subunit composition of postsynaptic receptors. Other studies have examined the mechanisms underlying chronic epilepsy initiated in early life. Models of both cortical dysplasia and recurrent early-life seizures suggest that alterations in the normal development of excitatory synaptic transmission can contribute importantly to chronic epileptic conditions. In the recurrent early-life seizure model, abnormal use-dependent selection of subpopulations of excitatory synapses may play a role. In experimental cortical dysplasia, alterations in the molecular composition of postsynaptic receptor are observed that favor subunit combinations characteristic of infancy.

Age Factors↗
PubMed2000

A role for sodium and chloride in kainic acid-induced beading of inhibitory interneuron dendrites.

Excitotoxic injury of the dendrites of inhibitory interneurons could lead to decreases in their synaptic activation and explain subsequent local circuit hyperexcitability and epilepsy. A hallmark of dendrotoxicity, at least in principal neurons of the hippocampus and cortex, is focal or varicose swellings of dendritic arbors. In experiments reported here, transient (1h) exposure of hippocampal explant cultures to kainic acid produced marked focal swellings of the dendrites of parvalbumin-immunoreactive pyramidal basket cells in a highly reproducible and dose-dependent manner. At 5mM kainic acid, more than half of the immunopositive apical dendrites in area CA(1) had a beaded appearance. However, the somal volumes of these cells were unaltered by the same treatment. The presence of focal swellings was reversible with kainate washout and was not accompanied by interneuronal cell death. In contrast, exposure to much higher concentrations (300mM) of kainic acid resulted in the total loss of parvalbumin-positive interneurons from explants. Surprisingly, kainic acid-induced dendritic beading does not appear to be mediated by extracellular calcium. Beading was unaltered in the presence of N-methyl-D-aspartate receptor antagonists, the L-type calcium channel antagonist, nimodipine, cadmium, or by removing extracellular calcium. However, blockade of voltage-gated sodium channels by either tetrodotoxin or lidocaine abolished dendritic beading, while the activation of existing voltage-gated sodium channels by veratridine mimicked the kainic acid-induced dendritic beading. Finally, the removal of extracellular chloride prevented the kainic acid-induced dendritic beading.Thus, we suggest that the movement of Na(+) and Cl(-), rather than Ca(2+), into cells underlies the focal swellings of interneuron dendrites in hippocampus.

Animals↗
PubMed2000

Neuronal platelet-activating factor receptor signal transduction involves a pertussis toxin-sensitive G-protein.

In most nonneural systems, platelet-activating factor (PAF) receptor effects are mediated by G-proteins that are often pertussis toxin-sensitive. The activation of pertussis toxin-sensitive G-proteins linked to PAF receptors results in the mobilization of intracellular calcium, at least in part, through the second messenger inositol triphosphate. We have sought to determine if a pertussis toxin-sensitive G-protein is involved in the PAF receptor-mediated phenomena of growth cone collapse and of synaptic enhancement in primary neuronal culture. Using infrared differential interference contrast microscopy and patch-clamp recording techniques, pertussis toxin, but not the inactive B oligomer of the toxin, was found to block both the growth cone collapse and the enhanced synaptic release of excitatory transmitter induced by a nonhydrolyzable PAF receptor agonist, making it likely that Go, Gq, or Gi is the G-protein transducer of PAF receptors in primary neurons. We believe that PAF acts directly on neuronal receptors, which are linked to pertussis toxin-sensitive G-proteins, on the tips of developing neurites, and on presynaptic nerve terminals, leading to growth cone collapse and enhanced synaptic release of transmitter.

Animals↗
PubMed1999

Insights into the tetanus toxin model of early-onset epilepsy from long-term video monitoring during anticonvulsant therapy.

Video monitoring studies were undertaken to determine if the anticonvulsant, carbamazepine (CBZ), could prevent seizures in infant rats that had been intrahippocampally injected with tetanus toxin (TNTX). In control rats, seizure frequency peaked 5-6 days after injection and rapidly declined by postinjection day 9. Twice-daily CBZ treatments dramatically suppressed behavioral seizures for 7 days. However, despite increasing the dosage of CBZ, rats experienced more behavioral seizures during the second week after TNTX injection. Paradoxically, tetanus-toxin-injected control rats had very few seizures at this time. Results not only suggest that this TNTX model may be useful in screening drugs for treating intractable focal epilepsy of infancy but also provide some insight into the processes that may contribute to the rapid decline in behavioral seizure frequency that occurs during the acute phase of epileptogenesis in this model.

Age of Onset↗
PubMed1999

Neuronal cytoskeletal alterations evoked by a platelet-activating factor (PAF) analogue.

Platelet-activating factor (PAF), a phospholipid signaling molecule found in brain, modulates several neural functions and is implicated in the human developmental brain disorder Miller-Dieker Lissencephaly (MDL). Exposure to PAF, and a non-hydrolyzable analogue, methyl carbamyl PAF (mc-PAF), produces the following rapid, reversible effects upon cultured hippocampal neurites: growth cone collapse, neurite retraction, and neurite varicosity formation. In this study, the cytoskeletal alterations that mediate these shape changes were investigated by comparing the effects of mc-PAF with other cytoskeletal-altering drugs, through the fluorescent labeling of cytoskeletal proteins and mitochondria, and by electron microscopy. Results indicate that rearrangements of microtubules (MTs), F-actin, and mitochondria underlie the neurite shape changes produced by mc-PAF. Evidence for MT alteration was obtained by comparing the effects of mc-PAF with nocodozole and taxol. Exposure to nocodazole, a MT-depolymerizing agent, produced growth cone collapse and neurite varicosity formation similar to mc-PAF, whereas pre-incubation of neurites in taxol, a MT-stabilizing drug, was effective in blocking mc-PAF-induced neurite effects. Immunofluorescent labeling and EM revealed MT splaying and unbundling within neurite varicosities following mc-PAF treatment. Immunofluorescent labeling also revealed that F-actin shifted from concentration in the growth cone to a diffuse distribution along the neurite shaft following mc-PAF exposure. Fluorescent labeling and EM also revealed retrograde movement and morphological alterations of mitochondria following mc-PAF exposure, resulting in mitochondrial aggregates within neurite varicosities. These cytoskeletal rearrangements may provide insights into the mechanisms by which PAF influences neuronal activity, and could have important implications for the impairment of neuronal motility observed in MDL.

Actins↗
PubMed1999

Long-term depression of perforant path excitatory postsynaptic potentials following synchronous network bursting in area CA3 of immature hippocampus.

Various forms of synaptic long-term potentiation and depression have been studied in detail in hippocampus and neocortex. Each are produced by specific patterns of synaptic activation and rely on electrical stimulation of afferents for their induction. Few studies have explored the ability of activity produced by cortical networks themselves to generate similar long-term changes in synaptic efficacy. Experiments have shown that periods of synchronized network bursting in both slices and dissociated cultures of hippocampus can lead to persistent network discharges. Conversely, one study has reported that network discharging can disrupt the induction of long-term potentiation in hippocampus. Whether long-term depression can be induced by synchronous network discharging is unknown. In experiments reported here, we examined the long-term effects of synchronized activity within hippocampal CA3 networks on synaptic potentials produced by the converging perforant path. Prior to induction of network bursting, slices were incubated in a perfusate containing picrotoxin and elevated (4 mM) Ca2+ and Mg2+. To induce network discharges, the concentration of both divalent cations were reduced to normal levels (1.5 mM). Following 20 min of network bursting, perforant path synapses, that did not participate in network discharging, underwent a 30% non-decrementing long-term depression. At the same time, synchronized network discharges, that were absent prior to induction, persisted upon return to preinduction conditions. The antagonist of the N-methyl-D-aspartate receptor, D(-)2-amino-5-phosphonovalerate, blocked both long-term depression of perforant path excitatory postsynaptic potentials and persistent network discharging. Results suggest that activity generated by hippocampal networks is able to produce long-term depression of non-coincidentally active synapses.

2-Amino-5-phosphonovalerate↗
PubMed1999

A chronic focal epilepsy with mossy fiber sprouting follows recurrent seizures induced by intrahippocampal tetanus toxin injection in infant rats.

Studies were conducted to characterize a chronic epileptic condition that follows recurrent seizures induced by intrahippocampal tetanus toxin injection in infancy. Wistar rat pups received a single injection of tetanus toxin in the right CA3 region on postnatal day 10. Animals were monitored for epileptiform activity by video electroencephalographic or visual observation during the following three to five days. Repeat evaluation six months later demonstrated interictal discharges in 79% (11 of 14) and electrographic seizures in 42% (six of 14) of adult rats with tetanus toxin-induced seizures in infancy. Five of the animals had interictal activity which occurred focally in either the left (n = 2) or right (n = 3) hippocampus. One animal had focal interictal activity independently in these regions and in the left and right cortical regions. The remaining five animals had interictal activity in the hippocampus and synchronously in the ipsilateral cortex or the contralateral hippocampus. Electrographic seizures were focal (nine of 14) or bilateral (five of 14) in onset. The behaviors that accompanied these seizures were quite variable. Clonic face and forelimb movements were observed in some animals. However, a significant portion of rats had electrographic seizures with no associated behavioral change. Timm staining was performed on hippocampal sections from experimental and control animals. There was a significantly greater Timm score (aberrant Timm granules) in the inner molecular layer of the dentate gyrus in tetanus toxin-treated rats than in control rats. Our findings suggest that intrahippocampal tetanus toxin injection in infant rats results in a chronic focal epilepsy that persists for at least six months and is associated with aberrant mossy fiber sprouting in the dentate gyrus. The model described here contributes significantly to the evidence for chronic effects of recurrent seizures in early life, and provides a model for investigation of the molecular and cellular events that contribute to the development of chronic epilepsy.

Aging↗
PubMed1999

Developmental neuroplasticity: roles in early life seizures and chronic epilepsy.

Both clinical and experimental studies suggest that the immature nervous system is unusually susceptible to seizures during critical periods in postnatal life. A late onset of gamma-aminobutyric acid (GABA)-mediated synaptic inhibition could conceivably play a contributing role in this phenomenon. Numerous studies have shown that neural systems that use GABA in the neonatal brain are different than those of adulthood. GABA is an excitatory neurotransmitter that likely plays a neurotrophic role in neuronal differentiation. Other reports suggest that unique, possibly transient, GABAergic interneuron populations exist in the embryonic and neonatal nervous system. At these early times in development, the immature nervous system is remarkably resistant to seizure generation. However, as the hippocampus and neocortex enter the critical period of enhanced seizure susceptibility, inhibitory GABA systems mature rapidly. At this time, blockade of GABA type A (GABAA) receptors produce unusually severe seizure discharges. In hippocampus, concurrent exuberant outgrowth of recurrent excitatory axon collaterals and synapses appear to play a role in the generation of these seizures. As the hippocampus matures, these axons are morphologically remodeled and nearly 50% of branches within arbors are pruned. This pruning of axon branches corresponds in time with the decrease in seizure susceptibility that characterizes adulthood. Developmental remodeling of neuronal connectivity is a common feature of most areas of the central nervous system. Results from an audiogenic seizure model of early onset epilepsy suggest that prevention of axon arbor remodeling by transient sensory deprivation can lead to a permanent overinnervation of target nuclei and chronic seizure susceptibility. Early life seizures may have a similar effect. Recent results in one model have shown that repeated seizures induced by intrahippocampal injections of tetanus toxin during a critical period results in a chronic epilepsy. Future studies should attempt to determine if the synchronized discharging of early-life seizures prevents the remodeling of neuronal connectivity that normally takes place during postnatal development and results in an overinnervated and chronically hyperexcitable hippocampus.

Aging↗
PubMed1998

Spine loss and other persistent alterations of hippocampal pyramidal cell dendrites in a model of early-onset epilepsy.

To explore the anatomical substrates for network hyperexcitability in adult rats that become chronically epileptic after recurrent seizures in infancy, the dendritic and axonal arbors of biocytin-filled hippocampal pyramidal cells were reconstructed. On postnatal day 10, tetanus toxin was unilaterally injected into the hippocampus and produced brief but recurrent seizures for 1 week. Later, hippocampal slices taken from these rats exhibited synchronized network bursts in area CA3C. Both the apical and basilar dendritic arbors of CA3C pyramidal cells were markedly abnormal in these epileptic rats. There was a considerable reduction in the density of dendrite spines, although the extent of this loss could vary among dendritic segments. Spine density on terminal segments of the basilar and apical dendrites was reduced on average by 35 and 20%, respectively. In addition, the diameters of these same dendritic segments were markedly reduced. Dendritic spine loss has previously been suggested to indicate a partial deafferentation of epileptic neurons, but this interpretation is difficult to reconcile with the critical role recurrent excitatory synaptic transmission plays in the generation of synchronized network burst. In this study, axonal arbors of CA3C pyramidal cells exhibited normal branching patterns, branching complexity, and varicosity density. This suggests that if deafferentation occurs, synapses other than recurrent excitatory ones are lost. The morphological abnormalities reported here would be expected to significantly alter electrical signaling within dendrites that may contribute importantly to seizures and other behavioral sequelae of early-onset epilepsy.

Action Potentials↗