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Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons.

Zhou C, Sun H, Klein PM, Jensen FE - Front Cell Neurosci (2015)

Bottom Line: Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg(2+) sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively.These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein.These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Division of Neuroscience, Boston Children's Hospital Boston, MA, USA ; Program in Neurobiology, Harvard Medical School Boston, MA, USA.

ABSTRACT
Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N-Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48-96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg(2+) sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain.

No MeSH data available.


Related in: MedlinePlus

Hypoxic seizures slightly increase GluN3A subunit expression in hippocampal CA1 neurons. (A) Representative Western blot of GluN3A subunit in micro-dissected hippocampus CA1 from control and 96 h post-HS rats. (B) Western blot quantification of total GluN3A subunit expression in micro-dissected hippocampus CA1 from control and 48–96 h post-HS rats (n = 10, 10, p = 0.075). Error bars indicate S.E.M.
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Figure 5: Hypoxic seizures slightly increase GluN3A subunit expression in hippocampal CA1 neurons. (A) Representative Western blot of GluN3A subunit in micro-dissected hippocampus CA1 from control and 96 h post-HS rats. (B) Western blot quantification of total GluN3A subunit expression in micro-dissected hippocampus CA1 from control and 48–96 h post-HS rats (n = 10, 10, p = 0.075). Error bars indicate S.E.M.

Mentions: Given decrease in Mg2+ sensitivity, we evaluated whether GluN3A protein expression in the CA1 region of P12–14 rats was altered after seizures at P10 (Figure 5). While there were no significant changes in total protein levels, we found a trend toward increased levels of GluN3A expression in 48–96 h post-HS group compared to their littermate controls (P12–14 controls: 100 ± 8.45%; 48–96 h post-HS rats: 127.41 ± 11.85%, n = 10, p = 0.075, Figure 5). At earlier time points there was no significant changes at 1–24 h post-HS (P10–11 controls: 100 ± 15.92%; 1–24 h post-HS rats: 118.11 ± 14.90%, n = 10, p = 0.41).


Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons.

Zhou C, Sun H, Klein PM, Jensen FE - Front Cell Neurosci (2015)

Hypoxic seizures slightly increase GluN3A subunit expression in hippocampal CA1 neurons. (A) Representative Western blot of GluN3A subunit in micro-dissected hippocampus CA1 from control and 96 h post-HS rats. (B) Western blot quantification of total GluN3A subunit expression in micro-dissected hippocampus CA1 from control and 48–96 h post-HS rats (n = 10, 10, p = 0.075). Error bars indicate S.E.M.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4585040&req=5

Figure 5: Hypoxic seizures slightly increase GluN3A subunit expression in hippocampal CA1 neurons. (A) Representative Western blot of GluN3A subunit in micro-dissected hippocampus CA1 from control and 96 h post-HS rats. (B) Western blot quantification of total GluN3A subunit expression in micro-dissected hippocampus CA1 from control and 48–96 h post-HS rats (n = 10, 10, p = 0.075). Error bars indicate S.E.M.
Mentions: Given decrease in Mg2+ sensitivity, we evaluated whether GluN3A protein expression in the CA1 region of P12–14 rats was altered after seizures at P10 (Figure 5). While there were no significant changes in total protein levels, we found a trend toward increased levels of GluN3A expression in 48–96 h post-HS group compared to their littermate controls (P12–14 controls: 100 ± 8.45%; 48–96 h post-HS rats: 127.41 ± 11.85%, n = 10, p = 0.075, Figure 5). At earlier time points there was no significant changes at 1–24 h post-HS (P10–11 controls: 100 ± 15.92%; 1–24 h post-HS rats: 118.11 ± 14.90%, n = 10, p = 0.41).

Bottom Line: Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg(2+) sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively.These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein.These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Division of Neuroscience, Boston Children's Hospital Boston, MA, USA ; Program in Neurobiology, Harvard Medical School Boston, MA, USA.

ABSTRACT
Neonatal seizures are commonly caused by hypoxic and/or ischemic injury during birth and can lead to long-term epilepsy and cognitive deficits. In a rodent hypoxic seizure (HS) model, we have previously demonstrated a critical role for seizure-induced enhancement of the AMPA subtype of glutamate receptor (GluA) in epileptogenesis and cognitive consequences, in part due to GluA maturational upregulation of expression. Similarly, as the expression and function of the N-Methyl-D-aspartate (NMDA) subtype of glutamate receptor (GluN) is also developmentally controlled, we examined how early life seizures during the critical period of synaptogenesis could modify GluN development and function. In a postnatal day (P)10 rat model of neonatal seizures, we found that seizures could alter GluN2/3 subunit composition of GluNs and physiological function of synaptic GluNs. In hippocampal slices removed from rats within 48-96 h following seizures, the amplitudes of synaptic GluN-mediated evoked excitatory postsynaptic currents (eEPSCs) were elevated in CA1 pyramidal neurons. Moreover, GluN eEPSCs showed a decreased sensitivity to GluN2B selective antagonists and decreased Mg(2+) sensitivity at negative holding potentials, indicating a higher proportion of GluN2A and GluN3A subunit function, respectively. These physiological findings were accompanied by a concurrent increase in GluN2A phosphorylation and GluN3A protein. These results suggest that altered GluN function and expression could potentially contribute to future epileptogenesis following neonatal seizures, and may represent potential therapeutic targets for the blockade of future epileptogenesis in the developing brain.

No MeSH data available.


Related in: MedlinePlus