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Yina Dong - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-
2016Co-Authors: Stage Alzheimer-type Tauopathy, Robert Siman, Ryan Cocca, Yina DongAbstract:The Perforant Pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer’s disease (AD) that may spread over time trans-synaptically. Despite the importance of the Perforant Pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of Perforant Pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral Perforant Pathway synapses in the dentate gyrus outer molec-ular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagi
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The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy.
PloS one, 2015Co-Authors: Robert Siman, Ryan Cocca, Yina DongAbstract:The Perforant Pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer’s disease (AD) that may spread over time trans-synaptically. Despite the importance of the Perforant Pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of Perforant Pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral Perforant Pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the Perforant Pathway, likely by preventing the synaptic spread of the AAV vector in response to Pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and Perforant Pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive gliosis. The findings support the potential for slowing the progression of AD by abrogating tau-mediated neurotoxicity at its earliest neuropathological stages.
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Rapamycin protects against tau-mediated lateral Perforant Pathway synapse loss.
2015Co-Authors: Robert Siman, Ryan Cocca, Yina DongAbstract:Timm staining in the dentate gyrus demarcates the afferent lamination of presynaptic terminal zinc. Left four panels, vehicle treatment: Contralateral to AAV vector injection (far left) in both blades of the dentate gyrus, zinc staining reveals a relatively dark zone in the outer molecular layer (OML) corresponding to the lateral entorhinal cortex and Perforant Pathway afferents. Neighboring afferent laminae in the stratum lacunosum-moleculare (SLM) above the hippocampal fissure (HF) for the suprapyramidal blade or the thalamus (THAL) for the infrapyramidal blade, or the middle molecular layer (MML) are demarcated by their lower synaptic zinc content. At 5 weeks after unilateral expression of pathological human tau in the lateral Perforant Pathway and treatment with vehicle, the lateral Perforant Pathway terminal field in the OML has largely degenerated in both blades of the ipsilateral dentate gyrus, concomitant with an expansion of the relatively zinc-poor medial Perforant Pathway afferents terminating in the MML. Right four panels, rapamycin treatment: Chronic rapamycin spares the relatively zinc-rich lateral Perforant Pathway synapses in the OML of both blades of the dentate gyrus. Scale bar = 40 μm.
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Rapamycin reduces pathological tau-triggered reactive microgliosis in the lateral Perforant Pathway synaptic field.
2015Co-Authors: Robert Siman, Ryan Cocca, Yina DongAbstract:Microglial activation triggered by pathological tau-induced neurodegeneration were distinguished from basal microglia based on their marked increase in immunohistochemical labeling for CR3/CD11b. (A) Cells with modest CR3 expression and the morphology of microglia (inset) were dispersed throughout the hippocampal dentate gyrus contralateral to viral vector delivery. (B) At 3 weeks after expression of pathological human tau in the lateral Perforant Pathway in mice treated with vehicle, dense bands of microglia with increased CR3 expression and enlarged processes were observed in the lateral Perforant Pathway terminal field in the outer molecular layer of both blades of the dentate gyrus. Whereas chronic rapamycin treatment did not appreciably alter basal CR3 expression in the contralateral hemisphere (C), it markedly attenuated the CR3 induction in reactive microglia in the lateral Perforant Pathway synaptic field (D). Abbreviations: HF- hippocampal fissure; OML- dentate outer molecular layer; MML- dentate middle molecular layer; IML- dentate inner molecular layer; GCL-dentate granule cell layer. Scale bar = 100 μm.
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Rapamycin inhibits pathological tau-activated innate immunity in the lateral Perforant Pathway synaptic field.
2015Co-Authors: Robert Siman, Ryan Cocca, Yina DongAbstract:Microglial-mediated innate immunity in response to pathological tau-induced neurodegeneration was evaluated by immunohistochemical labeling for mouse IgG. (A) Cells with modest IgG expression were dispersed throughout the hippocampal dentate gyrus contralateral to viral vector delivery. (B) At 3 weeks after expressing pathological human tau in the lateral Perforant Pathway in mice treated with vehicle, a dense band of microglia with increased IgG expression was observed in the dentate gyrus outer molecular layer. (C) The morphology of IgG-expressing cells confirmed their identification as microglia. Whereas chronic rapamycin treatment modestly reduced microglial IgG expression in the contralateral hemisphere (D), it markedly attenuated the reactive microgliosis-associated increase in IgG expression in the lateral Perforant Pathway synaptic field (E, low magnification; F, high magnification). Essentially identical findings were made in the infrapyramidal blade of the dentate gyrus. Scale bar = 20 μm (A,B,D,E), 10 μm (C,F).
Robert Siman - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH ARTICLE The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-
2016Co-Authors: Stage Alzheimer-type Tauopathy, Robert Siman, Ryan Cocca, Yina DongAbstract:The Perforant Pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer’s disease (AD) that may spread over time trans-synaptically. Despite the importance of the Perforant Pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of Perforant Pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral Perforant Pathway synapses in the dentate gyrus outer molec-ular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagi
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The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy.
PloS one, 2015Co-Authors: Robert Siman, Ryan Cocca, Yina DongAbstract:The Perforant Pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer’s disease (AD) that may spread over time trans-synaptically. Despite the importance of the Perforant Pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of Perforant Pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral Perforant Pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the Perforant Pathway, likely by preventing the synaptic spread of the AAV vector in response to Pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and Perforant Pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive gliosis. The findings support the potential for slowing the progression of AD by abrogating tau-mediated neurotoxicity at its earliest neuropathological stages.
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Rapamycin protects against tau-mediated lateral Perforant Pathway synapse loss.
2015Co-Authors: Robert Siman, Ryan Cocca, Yina DongAbstract:Timm staining in the dentate gyrus demarcates the afferent lamination of presynaptic terminal zinc. Left four panels, vehicle treatment: Contralateral to AAV vector injection (far left) in both blades of the dentate gyrus, zinc staining reveals a relatively dark zone in the outer molecular layer (OML) corresponding to the lateral entorhinal cortex and Perforant Pathway afferents. Neighboring afferent laminae in the stratum lacunosum-moleculare (SLM) above the hippocampal fissure (HF) for the suprapyramidal blade or the thalamus (THAL) for the infrapyramidal blade, or the middle molecular layer (MML) are demarcated by their lower synaptic zinc content. At 5 weeks after unilateral expression of pathological human tau in the lateral Perforant Pathway and treatment with vehicle, the lateral Perforant Pathway terminal field in the OML has largely degenerated in both blades of the ipsilateral dentate gyrus, concomitant with an expansion of the relatively zinc-poor medial Perforant Pathway afferents terminating in the MML. Right four panels, rapamycin treatment: Chronic rapamycin spares the relatively zinc-rich lateral Perforant Pathway synapses in the OML of both blades of the dentate gyrus. Scale bar = 40 μm.
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Rapamycin reduces pathological tau-triggered reactive microgliosis in the lateral Perforant Pathway synaptic field.
2015Co-Authors: Robert Siman, Ryan Cocca, Yina DongAbstract:Microglial activation triggered by pathological tau-induced neurodegeneration were distinguished from basal microglia based on their marked increase in immunohistochemical labeling for CR3/CD11b. (A) Cells with modest CR3 expression and the morphology of microglia (inset) were dispersed throughout the hippocampal dentate gyrus contralateral to viral vector delivery. (B) At 3 weeks after expression of pathological human tau in the lateral Perforant Pathway in mice treated with vehicle, dense bands of microglia with increased CR3 expression and enlarged processes were observed in the lateral Perforant Pathway terminal field in the outer molecular layer of both blades of the dentate gyrus. Whereas chronic rapamycin treatment did not appreciably alter basal CR3 expression in the contralateral hemisphere (C), it markedly attenuated the CR3 induction in reactive microglia in the lateral Perforant Pathway synaptic field (D). Abbreviations: HF- hippocampal fissure; OML- dentate outer molecular layer; MML- dentate middle molecular layer; IML- dentate inner molecular layer; GCL-dentate granule cell layer. Scale bar = 100 μm.
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Rapamycin inhibits pathological tau-activated innate immunity in the lateral Perforant Pathway synaptic field.
2015Co-Authors: Robert Siman, Ryan Cocca, Yina DongAbstract:Microglial-mediated innate immunity in response to pathological tau-induced neurodegeneration was evaluated by immunohistochemical labeling for mouse IgG. (A) Cells with modest IgG expression were dispersed throughout the hippocampal dentate gyrus contralateral to viral vector delivery. (B) At 3 weeks after expressing pathological human tau in the lateral Perforant Pathway in mice treated with vehicle, a dense band of microglia with increased IgG expression was observed in the dentate gyrus outer molecular layer. (C) The morphology of IgG-expressing cells confirmed their identification as microglia. Whereas chronic rapamycin treatment modestly reduced microglial IgG expression in the contralateral hemisphere (D), it markedly attenuated the reactive microgliosis-associated increase in IgG expression in the lateral Perforant Pathway synaptic field (E, low magnification; F, high magnification). Essentially identical findings were made in the infrapyramidal blade of the dentate gyrus. Scale bar = 20 μm (A,B,D,E), 10 μm (C,F).
Frank Angenstein - One of the best experts on this subject based on the ideXlab platform.
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Late effect of dopamine D1/5 receptor activation on stimulus-induced BOLD responses in the hippocampus and its target regions depends on the history of previous stimulations.
NeuroImage, 2017Co-Authors: Cornelia Helbing, Wolfgang Tischmeyer, Frank AngensteinAbstract:Abstract fMRI was used to study late effects of dopamine D 1/5 receptor activation on hippocampal signal processing and signal propagation to several target regions. The dopamine D 1/5 receptor agonists SKF83959 and SKF38393 were intraperitoneally applied without, immediately before or 7 days after electrical stimulation of the right Perforant Pathway with bursts of high-frequency pulses. Control animals received a 0.9% NaCl solution. One day after D 1/5 receptor activation, the Perforant Pathway was stimulated and the induced BOLD responses in the right hippocampus and its target regions, left hippocampus (l-HC) and medial prefrontal cortex (mPFC), were measured. Depending on the temporal relation between dopamine receptor activation and the first Perforant Pathway stimulation the induced BOLD response pattern differed. When applied without concurrent Perforant Pathway stimulation, the agonists caused region-selective increases in the induced BOLD responses: the effect of SKF83959 was evident in the mPFC whereas that of SKF38393 was confined to the l-HC. When applied in conjunction with Perforant Pathway stimulation, either agonist caused increased BOLD responses in both regions. In contrast, when applied 7 days after Perforant Pathway stimulation, neither SKF83959 nor SKF38393 modified the BOLD responses in the mPFC or l-HC 1 day later. These findings suggest that (i) activation of dopamine D 1/5 receptors alone is sufficient to modify stimulus-induced BOLD responses in target regions of the right hippocampus 24 h later, and (ii), the history of previous stimulations crucially affects the impact of dopamine receptor activation on stimulus-induced BOLD responses.
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The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat Perforant Pathway.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2015Co-Authors: Cornelia Helbing, Marta Brocka, Thomas Scherf, Michael T. Lippert, Frank AngensteinAbstract:Several human functional magnetic resonance imaging studies point to an activation of the mesolimbic dopamine system during reward, addiction and learning. We previously found activation of the mesolimbic system in response to continuous but not to discontinuous Perforant Pathway stimulation in an experimental model that we now used to investigate the role of dopamine release for the formation of functional magnetic resonance imaging responses. The two stimulation protocols elicited blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Inhibition of dopamine D1/5 receptors abolished the formation of functional magnetic resonance imaging responses in the medial prefrontal/anterior cingulate cortex during continuous but not during discontinuous pulse stimulations, i.e. only when the mesolimbic system was activated. Direct electrical or optogenetic stimulation of the ventral tegmental area caused strong dopamine release but only electrical stimulation triggered significant blood-oxygen level-dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. These functional magnetic resonance imaging responses were not affected by the D1/5 receptor antagonist SCH23390 but reduced by the N-methyl-D-aspartate receptor antagonist MK801. Therefore, glutamatergic ventral tegmental area neurons are already sufficient to trigger blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Although dopamine release alone does not affect blood-oxygen-level dependent responses it can act as a switch, permitting the formation of blood-oxygen-level dependent responses.
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Synchronized electrical stimulation of the rat medial forebrain bundle and Perforant Pathway generates an additive BOLD response in the nucleus accumbens and prefrontal cortex.
NeuroImage, 2013Co-Authors: Karla Krautwald, Hoon Ki Min, Kendall H. Lee, Frank AngensteinAbstract:To study how a synchronized activation of two independent Pathways affects the fMRI response in a common targeted brain region, blood oxygen dependent (BOLD) signals were measured during electrical stimulation of the right medial forebrain bundle (MFB), the right Perforant Pathway (PP) and concurrent stimulation of the two fiber systems. Repetitive electrical stimulations of the MFB triggered significant positive BOLD responses in the nucleus accumbens (NAcc), septum, anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), ventral tegmental area/substantia nigra (VTA/SN), right entorhinal cortex (EC) and colliculus superior, which, in general, declined during later stimulation trains. At the same time, negative BOLD responses were observed in the striatum. Thus, the same stimulus caused region-specific hemodynamic responses. An identical electrical stimulation of the PP generated positive BOLD responses in the right dentate gyrus/hippocampus proper/subiculum (DG/HC), the right entorhinal cortex and the left entorhinal cortex, which remained almost stable during consecutive stimulation trains. Co-stimulation of the two fiber systems resulted in an additive activation pattern, i.e., the BOLD responses were stronger during the stimulation of the two Pathways than during the stimulation of only one Pathway. However, during the simultaneous stimulation of the two Pathways, the development of the BOLD responses to consecutive trains changed. The BOLD responses in regions that were predominantly activated by MFB stimulation (i.e., NAcc, septum and ACC/mPFC) did not decline as fast as during pure MFB stimulation, thus an additive BOLD response was only observed during later trains. In contrast, in the brain regions that were predominantly activated by PP stimulation (i.e., right EC, DG/HC), co-stimulation of the MFB only resulted in an additive effect during early trains but not later trains. Consequently, the development of the BOLD responses during consecutive stimulations indicates the presence of an interaction between the two Pathways in a target region, whereas the observed averaged BOLD responses do not.
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variations in the temporal pattern of Perforant Pathway stimulation control the activity in the mesolimbic Pathway
NeuroImage, 2013Co-Authors: Cornelia Helbing, Grit Werner, Frank AngensteinAbstract:Signal processing in the hippocampal formation and resultant signal propagation to cortical and subcortical structures during high frequency stimulation (i.e. 100 Hz) of the Perforant Pathway was studied in medetomidine anesthetized rats by functional magnetic resonance imaging (fMRI) and electrophysiological recordings. The Perforant Pathway was stimulated with bursts of 20 pulses, one burst per second, or with continuously applied pulses. The stimulation duration was adjusted to 8 s (short) or 30 s (long). In general, extending the stimulation duration only caused a local spreading of the fMRI response, but no changes in the magnitude of the fMRI response. This was in agreement with the electrophysiological responses, which also remained unchanged. In contrast, increasing the number of pulses in one stimulus train (i.e. changing from burst to continuous stimulation), caused both spreading and an increase in local fMRI responses that were accompanied by an altered neuronal response pattern. Continuous stimulation also triggered additional fMRI responses in the septum, nucleus accumbens, anterior cingulate cortex/medial prefrontal cortex, and ventral tegmental area/substantia nigra. The appearance of fMRI responses outside the hippocampal formation required at least 3 consecutive stimulation trains, characterized by region specific hemodynamic response functions. Thus, once triggered, continuous stimulation caused a sequential appearance in fMRI responses starting in the hippocampal formation, followed by signal changes in the ventral tegmental area/substantia nigra and anterior cingulate cortex/medial prefrontal cortex and eventually in the nucleus accumbens. These results indicate that high frequency stimulation of the hippocampal formation can activate the mesolimbic Pathway, provided that repetitive stimulations are applied.
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Perforant Pathway stimulation as a conditioned stimulus for active avoidance learning triggers BOLD responses in various target regions of the hippocampus: a combined fMRI and electrophysiological study.
NeuroImage, 2013Co-Authors: Frank Angenstein, Karla Krautwald, Wolfram Wetzel, Henning ScheichAbstract:Functional magnetic resonance imaging and electrophysiology were combined to monitor blood oxygen level dependent (BOLD) signals in the entire rat brain and neuronal activities in the dentate gyrus during electrical stimulation of the right Perforant Pathway. In naive, medetomidine sedated animals, stimulation of the fiber bundle with 15 trains (i.e. 8 bursts of 20 pulses given with 10 ms intervals, one burst per second, pulse width 0.2 ms) generated significant BOLD responses in the right hippocampal formation and the left entorhinal cortex. The stimulation condition also caused changes in the synaptic efficacy of Perforant Pathway granular cell synapses that lasted for at least one day. Rerun of the same experiment one day later resulted in a significantly increased electrophysiological response in the dentate gyrus and an increase of the BOLD response in the entire hippocampal formation. Consequently, long-lasting changes in synaptic efficacy go along with changes in the generated BOLD response. Additional electrical stimulations of the Perforant Pathway in the awake animal between the two fMRI experiments caused in the second fMRI measurement an increased BOLD response in the hippocampal formation and an appearance of significant BOLD responses in target regions of the hippocampus, such as the septum, nucleus accumbens (NAcc), and anterior cingulate cortex/medial prefrontal cortex/motor cortex (ACC/mPFC/MC) regions. Consequently, the efficacy of signal processing in and propagation through the hippocampus can be monitored by variations of the BOLD response in target regions of the hippocampus. Using the electrical Perforant Pathway stimulations as conditioned stimulus for an active avoidance task (shuttle box) caused a further spreading of the BOLD response in the hippocampus formation, septum and ACC/mPFC/MC but not in the NAcc. In addition, the magnitude of the BOLD response in the trained animals was further increased in the right and left hippocampus and the ACC/mPFC/MC region but not in the septum. These results demonstrate that in addition to general stimulus parameter the behavioral relevance of the stimulus controls the quality of the generated BOLD response.
Cheryl A. Frye - One of the best experts on this subject based on the ideXlab platform.
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Finasteride blocks the reduction in ictal activity produced by exogenous estrous cyclicity.
Journal of neuroendocrinology, 2008Co-Authors: Cheryl A. Frye, Trudy J Scalise, Laura E. BayonAbstract:The purpose of the present study was to examine seizure activity during reduced 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) production. Ovariectomized Long-Evans rats were stereotaxically implanted with bipolar electrodes above the Perforant Pathway; silastic implants filled with estradiol-17-benzoate (EB) and progesterone were inserted subcutaneously to mimic diestrus. Estrus was then induced in half of these animals by injection of EB (30 microg) and progesterone (2.5 mg), 48 and 4 h, respectively, prior to Perforant Pathway stimulation. Half of the estrous and diestrous rats also received a 5alpha-reductase inhibitor, finasteride (50 mg/kg), 6 h prior to Perforant Pathway stimulation. The estrous condition was associated with reduced number and duration of partial seizures, improved performance on a Morris water maze recovery of function test, reduced neuronal loss in the hilar region of the hippocampus, and elevated central and plasma 3alpha,5alpha-THP, compared to estrus+finasteride, diestrus+vehicle and diestrus+finasteride conditions, which did not differ from each another. These data suggest antiseizure effects of estrus may be caused, in part, by the action of 3alpha,5alpha-THP and that the precipitous decline in 3alpha,5alpha-THP may restore seizure threshold to control levels.
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Anti-seizure effects of progesterone and 3α,5α-THP in kainic acid and Perforant Pathway models of epilepsy
Psychoneuroendocrinology, 2000Co-Authors: Cheryl A. Frye, Trudy J ScaliseAbstract:The mechanism by which progesterone has its anti-seizure effects is unknown. Progesterone has a high affinity for intracellular progestin receptors, but has weak actions at gamma-aminobutyric acid (GABA)(A) receptors complexes. The progesterone metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) is devoid of activity at intracellular progestin receptors but is a highly effective modulator of GABA(A) receptor complexes. Whether progesterones anti-seizure actions are due to effects of progesterone itself or its metabolite 3alpha,5alpha-THP was investigated. In experiment 1, 25 ovariectomized Long-Evans rats were subcutaneously (s.c.) injected with 0.0, 4.0 or 8.0 mg/kg progesterone or 3alpha,5alpha-THP, 10 min prior to systemic administration of 32 mg/kg kainic acid. Four and 8.0 mg/kg progesterone significantly reduced the duration of partial and full seizures, without influencing the latency to partial or full seizures, or the number of partial or full seizures. 3alpha, 5alpha-THP (4.0 mg/kg) significantly increased the latency to initial partial seizure, and decreased the number and duration of partial seizures. In experiment 2, 60 ovariectomized Long-Evans rats were stereotaxically implanted with bipolar electrodes into the Perforant Pathway. Prior to Perforant Pathway stimulation, rats were s.c. injected with either progesterone (4.0 mg/kg, n = 12), 3alpha, 5alpha-THP (4.0 mg/kg, n = 13), progesterone (4.0 mg/kg)+4MA (10.0 mg of a 5alpha-reductase inhibitor, 17b-N, N-diethylcarbamoyl-4-methyl-4-aza,5alpha-androstan-3-one, n = 12), 4MA+vehicle (n = 10), or sesame oil vehicle (n = 13). Administration of progesterone or 3alpha, 5alpha-THP, but not vehicle control, P+4MA, or 4MA, resulted in significant decreases in partial seizures. In experiment 3, whole brain progesterone and 3alpha,5alpha-THP were measured by radioimmunoassay in additional rats (n = 66) administered the hormonal milieu indicated in experiments 1 and 2. Data suggest anti-seizure effects of progesterone may be due, in part, to metabolism to 3alpha,5alpha-THP and subsequent actions at GABA(A) receptor complexes.
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Cyclic Withdrawal From Endogenous and Exogenous Progesterone Increases Kainic Acid and Perforant Pathway Induced Seizures
Pharmacology biochemistry and behavior, 1999Co-Authors: Cheryl A. Frye, Laura E. BayonAbstract:Abstract Antiseizure effects of progesterone (P) and its metabolite, 5α-pregnan-3α-ol-20-one (3α, 5α-THP) were investigated following continuous vs. discontinuous P exposure. In Experiments 1, 32 cycling Long–Evans rats were administered kainic acid (32 mg/kg SC), ictal behavior was examined, and plasma 3α,5α-THP levels were measured by radioimmunoassay. Proestrus/estrus rats showed less ictal activity and had elevated 3α,5α-THP levels prior to kainic acid compared to diestrus/metestrus subjects. In Experiment 2, 49 ovariectomized (ovx) rats were SC injected with estradiol benzoate (EB; 10 μg) and P (500 μg), to mimic estrus, or sesame oil vehicle (0.2 cc); all subjects were administered kainic acid. Rats tested with EB+P showed a reduced mean duration of full seizures and increased 3α,5α-THP, whereas those tested 24 h following EB+P had more tonic clonic seizures and lower 3α,5α-THP concentrations, comparable to ovx control animals. In Experiment 3, 49 ovx rats were stereotaxically implanted with bipolar electrodes into the Perforant Pathway. Prior to Perforant Pathway stimulation, rats received cholesterol or EB+P capsules for 1 month, continuously or intermittently. Irrespective of continuous or intermittent EB+P, the presence of progestins at the time of Perforant Pathway stimulation reduced partial seizure activity. Continuous EB+P capsules resulted in increased 3α,5α-THP levels compared to all other conditions, and less damage in the hilus of the hippocampus, compared to intermittent EB+P. These data confirm that P and 3α,5α-THP have antiseizure effects, and further suggest that repeated cycles of endogenous or exogenous P and/or 3α,5α-THP withdrawal influences seizure threshold and/or hippocampal integrity.
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the neurosteroid 3α 5α thp has antiseizure and possible neuroprotective effects in an animal model of epilepsy
Brain Research, 1995Co-Authors: Cheryl A. FryeAbstract:Abstract Some anticonvulsant drugs may suppress seizures by enhancing activity of GABAergic systems. Progesterone (P)'s anti-convulsant and neuroprotective effects may be due to the steroid's actions on GABAA-benzodiazepine receptor complexes (GBRs) rather than intracellular progestin receptors (PRs), as many P metabolites have a greater effect in vitro on benzodiazepine binding and Cl− flux than P, but poor affinity for PRs. If P's actions are due to metabolism to a progestin more potent at GBRs, then systemic administration of one of those P metabolites should also prevent CNS damage. To test this hypothesis male rats were implanted with a bipolar electrode, aimed above the Perforant Pathway. Experimental animals received the 5α-reduced P metabolite most effective at GBRs, 5α-pregnan-3α-ol-20-one (3α,5α-THP) 2.5 mg/kg s.c., 3 h prior to Perforant Pathway stimulation, while control animals received sesame oil vehicle. The duration of chewing and drooling, and the incidence of wet dog shakes, partial and full seizures were reduced during Perforant Pathway stimulation in animals pre-treated with 3α,5α-THP compared to vehicle. Two weeks later, animals pre-treated with 3α,5α-THP had shorter latencies and distances to find a hidden platform in a Morris Water maze task. 3α,5α-THP pre-treatment also reduced damage to CA1 and CA3 layers of the hippocampus and preserved the number of neurons in the hilar region. These data indicate that the neurosteroid metabolite of P, 3α,5α-THP, can have anticonvulsant and may have neuroprotective effects in an animal model of epilepsy. Further. these data suggest that the mechanism of P's protective and anticonvulsant effects may be via GBRs rather than PRs.
Robert S. Sloviter - One of the best experts on this subject based on the ideXlab platform.
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Hippocampal injury, atrophy, synaptic reorganization, and epileptogenesis after Perforant Pathway stimulation-induced status epilepticus in the mouse.
The Journal of comparative neurology, 2009Co-Authors: Friederike Kienzler, Braxton A. Norwood, Robert S. SloviterAbstract:Prolonged dentate granule cell discharges produce hippocampal injury and chronic epilepsy in rats. In preparing to study this epileptogenic process in genetically altered mice, we determined whether the background strain used to generate most genetically altered mice, the C57BL/6 mouse, is vulnerable to stimulation-induced seizure-induced injury. This was necessary because C57BL/6 mice are reportedly resistant to the neurotoxic effects of kainate-induced seizures, which we hypothesized to be related to strain differences in kainate’s effects, rather than genetic differences in intrinsic neuronal vulnerability. Bilateral Perforant Pathway stimulation-induced granule cell discharge for four hours under urethane anesthesia produced degeneration of GluR2-positive hilar mossy cells and peptide-containing interneurons in both FVB/N (kainate-vulnerable) and C57BL/6 (kainate-resistant) mice, indicating no strain differences in neuronal vulnerability to seizure activity. Granule cell discharge for two hours in C57BL/6 mice destroyed most GluR2-positive dentate hilar mossy cells, but not peptide-containing hilar interneurons, indicating that mossy cells are the neurons most vulnerable to this insult. Stimulation for 24 hours caused extensive hippocampal neuron loss and injury to the septum and entorhinal cortex, but no other detectable damage. Mice stimulated for 24 hours developed hippocampal sclerosis, granule cell mossy fiber sprouting, and chronic epilepsy, but not the granule cell layer hypertrophy (granule cell dispersion) produced by intrahippocampal kainate. These results demonstrate that Perforant Pathway stimulation in mice reliably reproduces the defining features of human mesial temporal lobe epilepsy with hippocampal sclerosis. Experimental studies in transgenic or knockout mice are feasible if electrical stimulation is used to produce controlled epileptogenic insults.
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Minimal latency to hippocampal epileptogenesis and clinical epilepsy after Perforant Pathway stimulation-induced status epilepticus in awake rats
The Journal of comparative neurology, 2008Co-Authors: Argyle V. Bumanglag, Robert S. SloviterAbstract:Hippocampal epileptogenesis is hypothesized to involve secondary mechanisms triggered by initial brain injury. Chemoconvulsant-induced status epilepticus has been used to identify secondary epileptogenic mechanisms under the assumption that a seizure-free, pre-epileptic “latent period” exists that is long enough to accommodate delayed mechanisms. The latent period is difficult to assess experimentally because early spontaneous seizures may be caused or influenced by residual chemoconvulsant that masks the true duration of the epileptogenic process. To avoid the use of chemoconvulsants and determine the latency to hippocampal epileptogenesis and clinical epilepsy, we developed an electrical stimulation-based method to evoke hippocampal discharges in awake rats, and produce hippocampal injury and hippocampal-onset epilepsy reliably. Continuous video-monitoring and granule cell layer recording determined whether hippocampal epileptogenesis develops immediately or long after injury. Bilateral Perforant Pathway stimulation for 3 hr evoked granule cell epileptiform discharges and convulsive status epilepticus with minimal lethality. Spontaneous Stage 3−5 behavioral seizures reliably developed within 3 days post-stimulation, and all 72 spontaneous behavioral seizures recorded in 10 animals were preceded by spontaneous granule cell epileptiform discharges. Histological analysis confirmed a reproducible pattern of limited hippocampal and extra-hippocampal injury, including an extensive bilateral loss of hilar neurons throughout the hippocampal longitudinal axis. These results indicate that hippocampal epileptogenesis after convulsive status epilepticus is an immediate network defect coincident with neuron loss or other early changes. We hypothesize that the latent period is directly related and inversely proportional to the extent of neuron loss in brain regions involved in seizure initiation, spread, and clinical expression.
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Neuronal hyperactivity induces astrocytic expression of neurocan in the adult rat hippocampus.
Glia, 2006Co-Authors: Stephan W. Schwarzacher, Carola A. Haas, Mario Vukšić, Guido J. Burbach, Robert S. Sloviter, Thomas DellerAbstract:Extracellular matrix molecules are involved in the cellular functions of proliferation, migration, morphological differentiation, and synaptic plasticity. One candidate molecule of the extracellular matrix is the chondroitin sulfate proteoglycan neurocan. To determine whether neurocan expression is regulated by neuronal activity in the adult rat brain, we studied changes in hippocampal neurocan mRNA and protein expression following electrical stimulation of the Perforant Pathway in urethane-anesthetized rats. After 24 h of intermittent, unilateral 20 Hz stimulation, in situ hybridization revealed increased neurocan mRNA in glial fibrillary acidic protein (GFAP)-positive astrocytes bilaterally in all hippocampal subfields. These changes were quantified in the dentate molecular layer, the termination zone of the Perforant Pathway, using laser microdissection in combination with quantitative reverse transcription-polymerase chain reaction (RT-PCR). Immediately after 24 h stimulation, a six-fold upregulation was detected, which returned to control levels by 3 days post-stimulation. Neurocan immunoreactivity was similarly upregulated bilaterally. Immunostaining intensity reached a maximum by 4 days and returned to control levels by 14 days. The pattern of neurocan expression in the hippocampus depended on the intensity and duration of electrical stimulation. Under conditions of less intense afferent stimulation (4-24 h of 2.0 Hz paired-pulse stimulation, interpulse interval 40 ms), increases in neurocan mRNA and immunoreactivity were restricted to the ipsilateral termination zone of the stimulated Perforant Pathway. This layer-specific neurocan upregulation was not affected by intraperitoneal application of the NMDA-receptor antagonist MK-801. In conclusion, our data indicate that synaptic activity regulates the astrocytic expression of neurocan in a graded manner.