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Biomedical subjects

Scott M Thompson

Publications and source records attributed to Scott M Thompson.

16 recordsLinked to original sources
PubMed2007

Hyperexcitability of distal dendrites in hippocampal pyramidal cells after chronic partial deafferentation.

Traumatic injury to the CNS results in chronic partial deafferentation of subsets of surviving neurons. Such injuries are often followed by a delayed but long-lasting period of aberrant hyperexcitability. The cellular mechanisms underlying this delayed hyperexcitability are poorly understood. We developed an in vitro model of deafferentation and reactive hyperexcitability using organotypic hippocampal slice cultures to study the underlying cellular mechanisms. One week after transection of the Schaffer collateral and temporoammonic afferents to CA1 neurons, brief tetanic stimulation of the residual excitatory synapses produced abnormally prolonged depolarizations, compared with responses in normally innervated neurons. Responses to weak stimulation, in contrast, were unaffected after deafferentation. Direct stimulation of distal apical dendrites using focal photolysis of caged glutamate triggered abnormally prolonged plateau potentials in the deafferented neurons when strong stimulation was given, but responses to weak stimulation were not different from controls. An identical phenotype was produced by chronic "chemical deafferentation" with glutamate receptor antagonists. Responses to strong synaptic and photolytic stimulation were selectively prolonged by small-conductance (SK-type) calcium-activated potassium channel blockers in normally innervated cells but not after deafferentation. No significant changes in SK2 mRNA or protein levels, GABAergic inhibition, glutamate receptor function, input resistance, or action potential parameters were observed after chronic deafferentation. We suggest that a posttranslational downregulation of SK channel function in thin distal dendrites is a significant contributor to deafferentation-induced reactive hyperexcitability.

Action Potentials↗
PubMed2006

Injury-induced axonal sprouting in the hippocampus is initiated by activation of trkB receptors.

Penetrating head injuries are often accompanied by the delayed development of post-traumatic epilepsy. Schaffer collateral transection leads to axonal sprouting and hyperexcitability in area CA3 of hippocampal slice cultures. We used this model to test the hypothesis that the injury-induced axonal sprouting results from increased neurotrophin signaling via trkB receptors near the lesion. Using rats and mice, we established that sprouting CA3 pyramidal cell axons are labeled with an antibody to the growth-associated protein GAP-43. We observed two- to threefold increases in the level of brain-derived neurotrophic factor and trkB protein in area CA3 by 24-48 h after Schaffer collateral transection, preceding the onset of axonal sprouting. Finally, we demonstrated that injury-induced axonal sprouting of GAP-43-immunoreactive axons is impaired in hippocampal slice cultures from mice expressing low levels of trkB receptors. We conclude that injury-induced axonal sprouting is initiated by brain-derived neurotrophic factor-trkB signaling and suggest that this process may be critical for the genesis of post-traumatic epilepsy.

Animals↗
PubMed2006

The growth compromised HSV-2 mutant DeltaRR prevents kainic acid-induced apoptosis and loss of function in organotypic hippocampal cultures.

We have previously shown that the HSV-2 anti-apoptotic protein ICP10PK is delivered by the replication incompetent virus mutant DeltaRR and prevents kainic acid (KA)-induced epileptiform seizures and neuronal cell loss in the mouse and rat models of temporal lobe epilepsy. The present studies used DeltaRR and the ICP10PK deleted virus mutant DeltaPK to examine the mechanism of neuroprotection. DeltaRR-infected neuronal cells expressed a chimeric protein in which ICP10PK is fused in frame to LacZ (p175) while retaining ICP10PK kinase activity. DeltaPK-infected neuronal cells expressed a mutant ICP10 protein that is deleted in the PK domain and is kinase negative (p95). p175 and p95 were expressed in CA3 (86+/-3%) and CA1 (69+/-7%) cells from DeltaRR or DeltaPK-infected organotypic hippocampal cultures (OHC) and 80-85% of the ICP10 positive cells co-stained with antibody to beta(III) Tubulin (neuronal marker). DeltaRR, but not DeltaPK, inhibited KA-induced cell death and caspase-3 activation in CA3 neurons, an inhibition seen whether DeltaRR was delivered 2 days before or 2 days after KA administration (95% neuroprotection). Neuroprotection was associated with ERK and Akt activation and was abrogated by simultaneous treatment with the MEK (U0126) and PI3-K (LY294002) inhibitors. DeltaRR-mediated neuroprotection was associated with increased expression of the anti-apoptotic protein Bag-1 and decreased expression of the pro-apoptotic protein Bad. The surviving neurons retained normal synaptic function potentially related to increased expression of the transcription factor CREB. The data indicate that DeltaRR is a promising platform for neuroprotection from excitotoxic injury.

Animals↗
PubMed2006

Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice.

Identification of targets and delivery platforms for gene therapy of neurodegenerative disorders is a clinical challenge. We describe a novel paradigm in which the neuroprotective gene is the herpes simplex virus type 2 (HSV-2) antiapoptotic gene ICP10PK and the vector is the growth-compromised HSV-2 mutant DeltaRR. DeltaRR is delivered intranasally. It is not toxic in rats and mice. ICP10PK is expressed in the hippocampus of the DeltaRR-treated animals for at least 42 days in the absence of virus replication and late virus gene expression. Its expression is regulated by an AP-1 amplification loop. Intranasally delivered DeltaRR prevents kainic acid-induced seizures, neuronal loss, and inflammation, in both rats and mice. The data suggest that DeltaRR is a promising therapeutic platform for neurodegenerative diseases.

Administration, Intranasal↗
PubMed2006

Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol.

Hypoxic/ischemic (HI) brain injury in newborn full-term and premature infants is a common and pervasive source of life time disabilities in cognitive and locomotor function. In the adult, HI induces glutamate release and excitotoxic cell death dependent on NMDA receptor activation. In animal models of the premature human infant, glutamate is also released following HI, but neurons are largely insensitive to NMDA or AMPA/kainic acid (KA) receptor-mediated damage. Using primary cultured hippocampal neurons we have determined that glutamate increases intracellular calcium much more than kainic acid. Moreover, glutamate induces cell death by activating Type I metabotropic glutamate receptors (mGluRs). Pretreatment of neurons with the gonadal steroid estradiol reduces the level of the Type I metabotropic glutamate receptors and completely prevents cell death, suggesting a novel therapeutic approach to excitotoxic brain damage in the neonate.

Animals↗
PubMed2006

A brief period of epileptiform activity strengthens excitatory synapses in the rat hippocampus in vitro.

PURPOSE: We examined here whether a very short period of epileptiform activity could produce lasting modifications of synaptic strength and network properties in the rat hippocampus in vitro. METHODS: Synaptic transmission at CA3-CA1 and at CA3-CA3 pyramidal cell synapses was monitored in hippocampal slice cultures before and after a very brief episode of epileptiform activity (20-180 s) induced with bicuculline methochloride. RESULTS: We show here that a brief period of epileptiform activity induces long-lasting potentiation of glutamatergic transmission at CA3-CA1 and at CA3-CA3 pyramidal cell synapses. This potentiation also was observed at synapses formed by pairs of monosynaptically connected neurons. It was dependent on N-methyl-d-aspartate (NMDA) receptors, occluded classic long-term potentiation, and could be depotentiated by low-frequency stimulation at 3 Hz. Recruitment of polysynaptic pathways within area CA3 was facilitated after epileptiform activity indicating that the induced potentiation enhanced overall hippocampal network excitability. CONCLUSIONS: These changes in synaptic transmission may contribute to the genesis of epilepsy and to seizure-associated memory deficits.

Animals↗
PubMed2005

Estradiol modulation of kainic acid-induced calcium elevation in neonatal hippocampal neurons.

The developing hippocampus of both males and females is exposed to high levels of the gonadal steroid estradiol. The impact of this estradiol exposure on developing hippocampal neurons is essentially unknown. In the rat, the newborn hippocampus is relatively insensitive to excitotoxic brain injury, which in adults is associated with the release of amino acids, in particular glutamate, resulting in a significant increase in intracellular calcium and eventual cell death. We have shown previously in the rat that administration of the glutamate agonist, kainic acid (KA), on the day of birth results in limited hippocampal damage, which is ameliorated by treatment with the gonadal steroid, estradiol. We now show that KA induces an increase in intracellular calcium through L-type voltage-sensitive calcium channels early in development and, later in development, through polyamine-sensitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with a modest increase through N-methyl-D-aspartate receptors. Pretreatment with the gonadal steroid, estradiol, decreases the percentage of neurons responding to KA and decreases the peak amplitude of the calcium transient early in development but has no effect later in development. Taken together, these data suggest that there is a developmental shift in the route of KA-induced intracellular calcium and estradiol modulates KA-induced intracellular calcium to a time restricted to early development, but whether this is the basis of the neuroprotective effect of estradiol remains to be determined.

Animals↗
PubMed2005

Long-term potentiation of exogenous glutamate responses at single dendritic spines.

Long-term increases in the strength of excitatory transmission at Schaffer collateral-CA1 cell synapses of the hippocampus require the insertion of new alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) into the synapse, but the kinetics of this process are not well established. Using microphotolysis of caged glutamate to activate receptors at single dendritic spines in hippocampal CA1 cells, we report the long-lasting potentiation of AMPAR-mediated currents with only a single pairing of photoreleased glutamate and brief postsynaptic depolarization. This potentiation was N-methyl-d-aspartate receptor (NMDAR)-dependent and was reversed with low-frequency photostimulation in an NMDAR-dependent manner, suggesting that it is mediated by the same mechanism(s) as conventional synaptic long-term potentiation. Potentiation of photolytic responses developed rapidly in a stepwise manner after a brief and variable delay (<60 s) at spines, but could not be induced at extrasynaptic sites on the dendritic shaft. Potentiation was accompanied by a concomitant decrease in postsynaptic, polyamine-dependent paired-pulse facilitation of the photolytic currents, indicating that a change in the subunit composition of the AMPARs underlying the response contributed to the potentiation. These changes are consistent with an increase in the proportion of GluR2-containing AMPARs in the spine head. These results demonstrate that activation of postsynaptic glutamate receptors by glutamate is not only necessary, but sufficient, for the induction of NMDAR-dependent long-term potentiation and reveal additional aspects of its expression.

Animals↗
PubMed2004

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.

4-Aminopyridine↗
PubMed2003

Activity-dependent activation of presynaptic protein kinase C mediates post-tetanic potentiation.

Vesicle exocytosis is mediated by the complex interaction between synaptic vesicle and plasma membrane proteins, many of which are substrates for protein kinases. Exogenous protein kinase activators increase release probability at several mammalian CNS synapses, but the physiological conditions under which presynaptic protein kinases become activated are not known. We report here that calcium/phospholipid-dependent protein kinase C (PKC) is activated by high-frequency stimulation and mediates post-tetanic potentiation (PTP) in the rat hippocampus.

Animals↗
PubMed2003

Activity-dependent release of adenosine contributes to short-term depression at CA3-CA1 synapses in rat hippocampus.

High-frequency stimulation results in a transient, presynaptically mediated decrease in synaptic efficacy called short-term depression (STD). Stimulation of Schaffer-collateral axons at 10 Hz for 5 s resulted in approximately 75% depression of excitatory postsynaptic current (EPSC) slope recorded from CA1 cells in rat organotypic slice cultures. An adenosine A(1) receptor antagonist decreased the magnitude of STD elicited with 10-Hz stimulation by approximately 30%. The A(1) receptor antagonist had no effect on STD elicited with 3-Hz stimulation. The activation of A(1) receptors during 10-Hz stimulation was not due to the extracellular conversion of released ATP to adenosine, because block of 5'-ectonucleotidases did not significantly affect STD. The adenosine transport inhibitor dipyridamole did not reduce STD, indicating that adenosine was not released by facilitated transport. We conclude that 10-Hz, but not 3-Hz, stimulation causes the vesicular release of adenosine and the rapid (<3 s) activation of presynaptic inhibitory A(1) receptors, which account for approximately 40% of homosynaptic EPSC depression.

Adenosine↗
PubMed2002

Short-term synaptic plasticity, simulation of nerve terminal dynamics, and the effects of protein kinase C activation in rat hippocampus.

Phorbol esters are hypothesised to produce a protein kinase C (PKC)-dependent increase in the probability of transmitter release via two mechanisms: facilitation of vesicle fusion or increases in synaptic vesicle number and replenishment. We used a combination of electrophysiology and computer simulation to distinguish these possibilities. We constructed a stochastic model of the presynaptic contacts between a pair of hippocampal pyramidal cells that used biologically realistic processes and was constrained by electrophysiological data. The model reproduced faithfully several forms of short-term synaptic plasticity, including short-term synaptic depression (STD), and allowed us to manipulate several experimentally inaccessible processes. Simulation of an increase in the size of the readily releasable vesicle pool and the time of vesicle replenishment decreased STD, whereas simulation of a facilitation of vesicle fusion downstream of Ca(2+) influx enhanced STD. Because activation of protein kinase C with phorbol ester enhanced STD of EPSCs in rat hippocampal slice cultures, we conclude that an increase in the sensitivity of the release process for Ca(2+) underlies the potentiation of neurotransmitter release by PKC.

Algorithms↗
PubMed2002

Physiological and morphological plasticity induced by chronic treatment with NT-3 or NT-4/5 in hippocampal slice cultures.

Expression of neurotrophins (NTs) and their receptors is elevated in the adult CNS under several neuropathological conditions. We have investigated the anatomical and electrophysiological consequences of chronic NT-3 or NT-4/5 treatment on established organotypic hippocampal slice cultures maintained in vitro for > 14 days. Both NT-3 and NT-4/5 increased spontaneous, action potential-dependent excitatory synaptic activity (sEPSCs), but only NT-3 increased inhibitory synaptic activity (sIPSCs) in CA3 pyramidal cells. Both NTs strongly promoted spontaneous synaptic bursting activity. Spontaneous bursts of EPSCs were observed after either NT treatment but only NT-3-treated cultures exhibited an increase in spontaneous bursts of IPSCs. In addition, sIPSC bursts were eliminated by blocking glutamatergic excitation. The frequency of miniature inhibitory postsynaptic currents, but not miniature excitatory postsynaptic currents, was also increased by both NT-3 and NT-4/5. Furthermore, NT-3 and NT-4/5 induced an up-regulation of the growth-associated protein GAP-43, suggesting that neurotrophins may be able to induce axonal reorganization in established neuronal networks. CA1 pyramidal cells exhibited slight alterations in dendritic branching after NT-4/5, but not NT-3 treatment. We conclude that chronic treatment with NT-3 or NT-4/5 can affect an established hippocampal network by elevating spontaneous inhibitory and excitatory synaptic activity and inducing coordinated pre- and postsynaptic structural changes.

Animals↗