Valerie Bracchi‐Ricard, Roberta Brambilla, Jonathan Levenson, Wen‐Hui Hu, Annmarie Bramwell, J. David Sweatt, Edward J. Green, John R. Bethea

Astrocytes play a pivotal role in regulating synaptic plasticity and synapse formation. The nuclear factor-kappa B (NF-kappaB) family of transcription factors has recently been demonstrated to be an important modulator of synaptic plasticity and learning/memory. In this study, we investigated the role of astroglial NF-kappaB in synaptic plasticity and learning/memory using transgenic mice over-expressing an N-terminal truncated form of inhibitor of NF-kappaB alpha (IkappaBalpha) in astrocytes (GFAP-IkappaBetaalpha-dn). We demonstrated that female transgenic mice, but not males, have robust deficits in hippocampal and extra-hippocampal-dependent learning and memory. We also determined that there are significant deficits in LTP and expression of metabotropic glutamate receptor 5 and post-synaptic density protein 95 (PSD95) in female transgenic mice. These findings indicate that astroglial NF-kappaB is an important regulator of learning/memory and synaptic plasticity.