Creb-dependent transcriptional control and quantal changes in persistent long-term potentiation in hippocampal interneurons

Abstract

Mounting evidence indicates an important role of long-term synaptic plasticity in hippocampal inhibitory interneurons in learning and memory. The cellular and molecular mechanisms that underlie such persistent changes in synaptic function in interneurons remain, however, largely undetermined. Atranscription- and translation-dependent form oflong-term potentiation was uncoveredat excitatory synapses onto hippocampal interneurons in oriens-alveus (OA-INs) which is induced by activation of type 1 metabotropic glutamate receptors (cL-LTPmGluR1). Here, we use (1) a combination of pharmacological siRNA knock-down and overexpression approaches to reveal the molecular mechanisms of transcriptional control via cAMP response element-binding protein (CREB) during induction, and (2) quantal analysis to identify synaptic changes during maintenance of cL-LTPmGluR1 in rat hippocampus. Induction stimulated CREB phosphorylation in OA-INs via extracellular signal-regulated protein kinase (ERK) signaling. Also, CREB knockdown impaired cL-LTPmGluR1, whereas CREB over expression facilitated the induction, demonstrating a necessary and permissive role of CREB via ERK signaling in transcriptional control in cL-LTPmGluR1. Quantal analysis of synaptic responses during cL-LTPmGluR1 maintenance revealed an increased number of quanta released, corresponding to enhanced transmitter release and a larger quantal size, indicating enhanced responsiveness to individual quanta. Fluctuation analysis of synaptic currents uncovered an increase in conductance and number of functional postsynaptic receptors contributing to single quanta. Our findings indicate that CREB-dependent transcription isa necessary permissive switch for eliciting persistent presynaptic and postsynaptic quantal changes at excitatory synapses ininhibitory local circuits, uncovering cell type-specific coupling of induction and expression mechanisms during persistent synaptic plasticity which may contribute to hippocampal long-term memory processes. © 2012 the authors.