TY - JOUR
T1 - NF-κB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity
AU - O'Mahony, Alison
AU - Raber, Jacob
AU - Montano, Mauricio
AU - Foehr, Erik
AU - Han, Victor
AU - Lu, Shao Ming
AU - Kwon, Hakju
AU - LeFevour, Anthony
AU - Chakraborty-Sett, Shikha
AU - Greene, Warner C.
PY - 2006/10
Y1 - 2006/10
N2 - Changes in synaptic plasticity required for memory formation are dynamically regulated through opposing excitatory and inhibitory neurotransmissions. To explore the potential contribution of NF-κB/Rel to these processes, we generated transgenic mice conditionally expressing a potent NF-κB/Rel inhibitor termed IκBα superrepressor (IκBα-SR). Using the prion promoter-enhancer, IκBα-SR is robustly expressed in inhibitory GABAergic interneurons and, at lower levels, in excitatory neurons but not in glia. This neuronal pattern of IκBα-SR expression leads to decreased expression of glutamate decarboxylase 65 (GAD65), the enzyme required for synthesis of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA) in GABAergic interneurons. IκBα-SR expression also results in diminished basal GluR1 levels and impaired synaptic strength (input/output function), both of which are fully restored following activity-based task learning. Consistent with diminished GAD65-derived inhibitory tone and enhanced excitatory firing, IκBα-SR+ mice exhibit increased late-phase long-term potentiation, hyperactivity, seizures, increased exploratory activity, and enhanced spatial learning and memory. IκBα-SR+ neurons also express higher levels of the activity-regulated, cytoskeleton-associated (Arc) protein, consistent with neuronal hyperexcitability. These findings suggest that NF-κB/Rel transcription factors act as pivotal regulators of activity-dependent inhibitory and excitatory neuronal function regulating synaptic plasticity and memory.
AB - Changes in synaptic plasticity required for memory formation are dynamically regulated through opposing excitatory and inhibitory neurotransmissions. To explore the potential contribution of NF-κB/Rel to these processes, we generated transgenic mice conditionally expressing a potent NF-κB/Rel inhibitor termed IκBα superrepressor (IκBα-SR). Using the prion promoter-enhancer, IκBα-SR is robustly expressed in inhibitory GABAergic interneurons and, at lower levels, in excitatory neurons but not in glia. This neuronal pattern of IκBα-SR expression leads to decreased expression of glutamate decarboxylase 65 (GAD65), the enzyme required for synthesis of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA) in GABAergic interneurons. IκBα-SR expression also results in diminished basal GluR1 levels and impaired synaptic strength (input/output function), both of which are fully restored following activity-based task learning. Consistent with diminished GAD65-derived inhibitory tone and enhanced excitatory firing, IκBα-SR+ mice exhibit increased late-phase long-term potentiation, hyperactivity, seizures, increased exploratory activity, and enhanced spatial learning and memory. IκBα-SR+ neurons also express higher levels of the activity-regulated, cytoskeleton-associated (Arc) protein, consistent with neuronal hyperexcitability. These findings suggest that NF-κB/Rel transcription factors act as pivotal regulators of activity-dependent inhibitory and excitatory neuronal function regulating synaptic plasticity and memory.
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U2 - 10.1128/MCB.00510-06
DO - 10.1128/MCB.00510-06
M3 - Article
C2 - 16980629
AN - SCOPUS:33749181999
SN - 0270-7306
VL - 26
SP - 7283
EP - 7298
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 19
ER -