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Hippocampal neuro-networks and dendritic spine perturbations in epileptogenesis are attenuated by neuroprotectin d1.

Musto AE, Walker CP, Petasis NA, Bazan NG - PLoS ONE (2015)

Bottom Line: We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis.Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures.Our results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.

ABSTRACT

Purpose: Limbic epileptogenesis triggers molecular and cellular events that foster the establishment of aberrant neuronal networks that, in turn, contribute to temporal lobe epilepsy (TLE). Here we have examined hippocampal neuronal network activities in the pilocarpine post-status epilepticus model of limbic epileptogenesis and asked whether or not the docosahexaenoic acid (DHA)-derived lipid mediator, neuroprotectin D1 (NPD1), modulates epileptogenesis.

Methods: Status epilepticus (SE) was induced by intraperitoneal administration of pilocarpine in adult male C57BL/6 mice. To evaluate simultaneous hippocampal neuronal networks, local field potentials were recorded from multi-microelectrode arrays (silicon probe) chronically implanted in the dorsal hippocampus. NPD1 (570 μg/kg) or vehicle was administered intraperitoneally daily for five consecutive days 24 hours after termination of SE. Seizures and epileptiform activity were analyzed in freely-moving control and treated mice during epileptogenesis and epileptic periods. Then hippocampal dendritic spines were evaluated using Golgi-staining.

Results: We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis. These aberrant activities were attenuated following systemic NPD1 administration, with concomitant hippocampal dendritic spine protection. Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures.

Conclusions: Our results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis. Insight into the molecular signaling mediated by neuroprotective bioactivity of NPD1 on neuronal network dysfunction may contribute to the development of anti-epileptogenic therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus

Neuroprotectin D1 induces sustained protection of dendritic spines during epileptogenesis.A: Representative dendrites from control (naïve) and a mouse at 7 days after status epilepticus (SE) from CA1, stratum radiatum (RAD), dentate gyrus (DG) and outer molecular layer (OM). B: Note loss of number of dendritic spines as a consequence of status epilepticus (PSE, n = 3) compared with control (n = 3). C: High-power light magnification of dendrite profiles of CA1 and dentate gyrus (DG) regions showing dendritic beadings in vehicle-treated mice (n = 4) (arrows) and lower dendritic spine profiles compared with NPD1-treated mice (n = 4) in epileptogenesis D: NPD1-treated mice show a higher number of dendritic spines in the hippocampal layers than vehicle. E: Number of dendritic beadings per dendrites is reduced in NPD1-treated mice compared with vehicle. Bars indicate means, and error bars represent S.E.M. p = p value. *: p<0.05, two sample t-test.
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pone.0116543.g007: Neuroprotectin D1 induces sustained protection of dendritic spines during epileptogenesis.A: Representative dendrites from control (naïve) and a mouse at 7 days after status epilepticus (SE) from CA1, stratum radiatum (RAD), dentate gyrus (DG) and outer molecular layer (OM). B: Note loss of number of dendritic spines as a consequence of status epilepticus (PSE, n = 3) compared with control (n = 3). C: High-power light magnification of dendrite profiles of CA1 and dentate gyrus (DG) regions showing dendritic beadings in vehicle-treated mice (n = 4) (arrows) and lower dendritic spine profiles compared with NPD1-treated mice (n = 4) in epileptogenesis D: NPD1-treated mice show a higher number of dendritic spines in the hippocampal layers than vehicle. E: Number of dendritic beadings per dendrites is reduced in NPD1-treated mice compared with vehicle. Bars indicate means, and error bars represent S.E.M. p = p value. *: p<0.05, two sample t-test.

Mentions: Because LFPs represent post-synaptic potential activities from synchronized neurons [21], and since dendritic spines are thought to be a morphological signature of post-synaptic sites [36] and a key target for neuronal network assemblies damaged during epilepsy [37], we asked whether MEAs were associated with hippocampal dendritic spine modification. Using Golgi staining, we observed a reduction of the number of dendritic spines per dendrite segment in CA1 and dentate gyrus regions (Fig. 7A, B, RAD: Control: 0.78 ± 0.06 S.E.M. vs. Epileptogenesis: 0.62 ± 0.03 S.E.M., p = 0.03; DG: Control: 0.82 ± 0.054 S.E.M. vs. Epileptogenesis: 0.67 ± 0.03 S.E.M., p = 0.02) after 7 days of SE. Also, dendritic swelling and beading, both of which are hallmarks of dendritic injury [38], were present as a consequence of SE. Using the same histological approach, we observed, at seven days after SE, that NPD1 administration showed higher density of spines from the dendrites of both CA1 PYR and DG-granular cells compared to vehicle-treated mice (OR: NPD1: 0.90 ± 0.04 S.E.M. vs. Vehicle: 0.69 ± 0.03 S.E.M., p = 0.0007; RAD: NPD1: 1.04 ± 0.05 S.E.M. vs. Vehicle: 0.83 ± 0.04 S.E.M. p = 0.03; L-M: NPD1: 0.93 ± 0.64 S.E.M. vs. Vehicle: 0.64 ± 0.03 S.E.M., p = 0.0001; DG: NPD1: 1.07 ± 0.05 S.E.M. vs. Vehicle: 0.80 ± 0.05 S.E.M., p = 0.009; Fig. 7 C, D) and induced less beading-like profiles (CA1: NPD1: 0.65 ± 0.16 S.E.M vs. Vehicle: 3.44 ± 0.41 S.E.M.; DG: NPD1 0.65 ± 0016 S.E.M. vs. Vehicle: 3.44± 0.39 S.E.M., p;<0.0001; Fig. 7 E).


Hippocampal neuro-networks and dendritic spine perturbations in epileptogenesis are attenuated by neuroprotectin d1.

Musto AE, Walker CP, Petasis NA, Bazan NG - PLoS ONE (2015)

Neuroprotectin D1 induces sustained protection of dendritic spines during epileptogenesis.A: Representative dendrites from control (naïve) and a mouse at 7 days after status epilepticus (SE) from CA1, stratum radiatum (RAD), dentate gyrus (DG) and outer molecular layer (OM). B: Note loss of number of dendritic spines as a consequence of status epilepticus (PSE, n = 3) compared with control (n = 3). C: High-power light magnification of dendrite profiles of CA1 and dentate gyrus (DG) regions showing dendritic beadings in vehicle-treated mice (n = 4) (arrows) and lower dendritic spine profiles compared with NPD1-treated mice (n = 4) in epileptogenesis D: NPD1-treated mice show a higher number of dendritic spines in the hippocampal layers than vehicle. E: Number of dendritic beadings per dendrites is reduced in NPD1-treated mice compared with vehicle. Bars indicate means, and error bars represent S.E.M. p = p value. *: p<0.05, two sample t-test.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4305283&req=5

pone.0116543.g007: Neuroprotectin D1 induces sustained protection of dendritic spines during epileptogenesis.A: Representative dendrites from control (naïve) and a mouse at 7 days after status epilepticus (SE) from CA1, stratum radiatum (RAD), dentate gyrus (DG) and outer molecular layer (OM). B: Note loss of number of dendritic spines as a consequence of status epilepticus (PSE, n = 3) compared with control (n = 3). C: High-power light magnification of dendrite profiles of CA1 and dentate gyrus (DG) regions showing dendritic beadings in vehicle-treated mice (n = 4) (arrows) and lower dendritic spine profiles compared with NPD1-treated mice (n = 4) in epileptogenesis D: NPD1-treated mice show a higher number of dendritic spines in the hippocampal layers than vehicle. E: Number of dendritic beadings per dendrites is reduced in NPD1-treated mice compared with vehicle. Bars indicate means, and error bars represent S.E.M. p = p value. *: p<0.05, two sample t-test.
Mentions: Because LFPs represent post-synaptic potential activities from synchronized neurons [21], and since dendritic spines are thought to be a morphological signature of post-synaptic sites [36] and a key target for neuronal network assemblies damaged during epilepsy [37], we asked whether MEAs were associated with hippocampal dendritic spine modification. Using Golgi staining, we observed a reduction of the number of dendritic spines per dendrite segment in CA1 and dentate gyrus regions (Fig. 7A, B, RAD: Control: 0.78 ± 0.06 S.E.M. vs. Epileptogenesis: 0.62 ± 0.03 S.E.M., p = 0.03; DG: Control: 0.82 ± 0.054 S.E.M. vs. Epileptogenesis: 0.67 ± 0.03 S.E.M., p = 0.02) after 7 days of SE. Also, dendritic swelling and beading, both of which are hallmarks of dendritic injury [38], were present as a consequence of SE. Using the same histological approach, we observed, at seven days after SE, that NPD1 administration showed higher density of spines from the dendrites of both CA1 PYR and DG-granular cells compared to vehicle-treated mice (OR: NPD1: 0.90 ± 0.04 S.E.M. vs. Vehicle: 0.69 ± 0.03 S.E.M., p = 0.0007; RAD: NPD1: 1.04 ± 0.05 S.E.M. vs. Vehicle: 0.83 ± 0.04 S.E.M. p = 0.03; L-M: NPD1: 0.93 ± 0.64 S.E.M. vs. Vehicle: 0.64 ± 0.03 S.E.M., p = 0.0001; DG: NPD1: 1.07 ± 0.05 S.E.M. vs. Vehicle: 0.80 ± 0.05 S.E.M., p = 0.009; Fig. 7 C, D) and induced less beading-like profiles (CA1: NPD1: 0.65 ± 0.16 S.E.M vs. Vehicle: 3.44 ± 0.41 S.E.M.; DG: NPD1 0.65 ± 0016 S.E.M. vs. Vehicle: 3.44± 0.39 S.E.M., p;<0.0001; Fig. 7 E).

Bottom Line: We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis.Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures.Our results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.

ABSTRACT

Purpose: Limbic epileptogenesis triggers molecular and cellular events that foster the establishment of aberrant neuronal networks that, in turn, contribute to temporal lobe epilepsy (TLE). Here we have examined hippocampal neuronal network activities in the pilocarpine post-status epilepticus model of limbic epileptogenesis and asked whether or not the docosahexaenoic acid (DHA)-derived lipid mediator, neuroprotectin D1 (NPD1), modulates epileptogenesis.

Methods: Status epilepticus (SE) was induced by intraperitoneal administration of pilocarpine in adult male C57BL/6 mice. To evaluate simultaneous hippocampal neuronal networks, local field potentials were recorded from multi-microelectrode arrays (silicon probe) chronically implanted in the dorsal hippocampus. NPD1 (570 μg/kg) or vehicle was administered intraperitoneally daily for five consecutive days 24 hours after termination of SE. Seizures and epileptiform activity were analyzed in freely-moving control and treated mice during epileptogenesis and epileptic periods. Then hippocampal dendritic spines were evaluated using Golgi-staining.

Results: We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis. These aberrant activities were attenuated following systemic NPD1 administration, with concomitant hippocampal dendritic spine protection. Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures.

Conclusions: Our results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis. Insight into the molecular signaling mediated by neuroprotective bioactivity of NPD1 on neuronal network dysfunction may contribute to the development of anti-epileptogenic therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus