Limits...
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 (HSs) enhance GluN function in hippocampal CA1 pyramidal neurons from P10 to P17. (A) Representative traces of GluN-mediated eEPSCs, pharmacologically isolated by blocking GluA and GABAA receptors, at a holding potential of +40 mV in hippocampal ex vivo slices from control and 96 h post-HS rats. (B) GluN-mediated eEPSC amplitude is significantly larger in neurons from 48–96 h post-HS rats (p < 0.05, n = 11 cells), but not in neurons from 1–24 h post-HS rats (p > 0.05, n = 11 cells) and 1 week post-HS rats (p > 0.05, n = 6 cells), compared to littermate control rats (n = 6–10 cells). *p < 0.05. Error bars indicate S.E.M.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585040&req=5

Figure 1: Hypoxic seizures (HSs) enhance GluN function in hippocampal CA1 pyramidal neurons from P10 to P17. (A) Representative traces of GluN-mediated eEPSCs, pharmacologically isolated by blocking GluA and GABAA receptors, at a holding potential of +40 mV in hippocampal ex vivo slices from control and 96 h post-HS rats. (B) GluN-mediated eEPSC amplitude is significantly larger in neurons from 48–96 h post-HS rats (p < 0.05, n = 11 cells), but not in neurons from 1–24 h post-HS rats (p > 0.05, n = 11 cells) and 1 week post-HS rats (p > 0.05, n = 6 cells), compared to littermate control rats (n = 6–10 cells). *p < 0.05. Error bars indicate S.E.M.

Mentions: We examined whether early life HS could alter GluN function as the NMDA subtype of glutamate receptor expression undergoes significant differential regulation during postnatal development (Rakhade and Jensen, 2009). GluN receptors critically contribute to neuronal excitability and seizures (Ghasemi and Schachter, 2011), and in turn they can be altered by neuronal activity (Sanchez et al., 2000; Yashiro and Philpot, 2008; Clasadonte et al., 2013). In this study, we measured evoked GluN-mediated excitatory postsynaptic currents (GluN eEPSCs) from hippocampal CA1pyramidal neurons from 1 h to 7 days post-HS neonatal rats and their littermate controls. GluN eEPSCs in hippocampal CA1 pyramidal neurons showed a peak in amplitude around postnatal (P) 12–14 in both normoxic control rats and post-HS rats (Figures 1A,B). In contrast, GluN eEPSCs showed significantly higher amplitudes in CA1 pyramidal neurons from 48–96 h post-HS rats compared to controls (post-HS 48–96 h: 52.51 ± 6.28pA, n = 11 cells vs P12–14 normoxic controls: 29.98 ± 3.84pA, n = 10 cells, p = 0.002, Figures 1A,B), while no significant changes were found at earlier (1–24 h) or later (7 days) time points post HS (n = 10–11 cells, p > 0.05). These results demonstrate a transient enhancement in GluN eEPSC amplitude following HS in the developing brain, suggesting that function of GluNs during postnatal 48–96 h is sensitive to early hypoxia-induced seizures.


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 (HSs) enhance GluN function in hippocampal CA1 pyramidal neurons from P10 to P17. (A) Representative traces of GluN-mediated eEPSCs, pharmacologically isolated by blocking GluA and GABAA receptors, at a holding potential of +40 mV in hippocampal ex vivo slices from control and 96 h post-HS rats. (B) GluN-mediated eEPSC amplitude is significantly larger in neurons from 48–96 h post-HS rats (p < 0.05, n = 11 cells), but not in neurons from 1–24 h post-HS rats (p > 0.05, n = 11 cells) and 1 week post-HS rats (p > 0.05, n = 6 cells), compared to littermate control rats (n = 6–10 cells). *p < 0.05. Error bars indicate S.E.M.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Hypoxic seizures (HSs) enhance GluN function in hippocampal CA1 pyramidal neurons from P10 to P17. (A) Representative traces of GluN-mediated eEPSCs, pharmacologically isolated by blocking GluA and GABAA receptors, at a holding potential of +40 mV in hippocampal ex vivo slices from control and 96 h post-HS rats. (B) GluN-mediated eEPSC amplitude is significantly larger in neurons from 48–96 h post-HS rats (p < 0.05, n = 11 cells), but not in neurons from 1–24 h post-HS rats (p > 0.05, n = 11 cells) and 1 week post-HS rats (p > 0.05, n = 6 cells), compared to littermate control rats (n = 6–10 cells). *p < 0.05. Error bars indicate S.E.M.
Mentions: We examined whether early life HS could alter GluN function as the NMDA subtype of glutamate receptor expression undergoes significant differential regulation during postnatal development (Rakhade and Jensen, 2009). GluN receptors critically contribute to neuronal excitability and seizures (Ghasemi and Schachter, 2011), and in turn they can be altered by neuronal activity (Sanchez et al., 2000; Yashiro and Philpot, 2008; Clasadonte et al., 2013). In this study, we measured evoked GluN-mediated excitatory postsynaptic currents (GluN eEPSCs) from hippocampal CA1pyramidal neurons from 1 h to 7 days post-HS neonatal rats and their littermate controls. GluN eEPSCs in hippocampal CA1 pyramidal neurons showed a peak in amplitude around postnatal (P) 12–14 in both normoxic control rats and post-HS rats (Figures 1A,B). In contrast, GluN eEPSCs showed significantly higher amplitudes in CA1 pyramidal neurons from 48–96 h post-HS rats compared to controls (post-HS 48–96 h: 52.51 ± 6.28pA, n = 11 cells vs P12–14 normoxic controls: 29.98 ± 3.84pA, n = 10 cells, p = 0.002, Figures 1A,B), while no significant changes were found at earlier (1–24 h) or later (7 days) time points post HS (n = 10–11 cells, p > 0.05). These results demonstrate a transient enhancement in GluN eEPSC amplitude following HS in the developing brain, suggesting that function of GluNs during postnatal 48–96 h is sensitive to early hypoxia-induced seizures.

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