A Cooperative Mechanism Involving Ca2+-Permeable AMPA Receptors and Retrograde Activation of GABAB Receptors in Interpeduncular Nucleus Plasticity

Summary: The medial habenula-interpeduncular nucleus (MHb-IPN) pathway, which connects the limbic forebrain to the midbrain, has recently been implicated in aversive behaviors. The MHb-IPN circuit is characterized by a unique topographical organization, an excitatory role of GABA, and a prominent co-release of neurotransmitters and neuropeptides. However, little is known about synaptic plasticity in this pathway. An application of a high-frequency stimulation resulted in a long-lasting potentiation of glutamate release in IPN neurons. Our experiments reveal that a Ca2+-permeable AMPA receptor (CPAR)-dependent release of GABA from IPN neurons and a retrograde activation of GABAB receptors on MHb terminals result in a long-lasting enhancement of glutamate release. Strikingly, adolescent IPN neurons lacked CPARs and exhibited an inability to undergo plasticity. In addition, fear conditioning suppressed an activity-dependent potentiation of MHb-IPN synapses, whereas fear extinction reversed this plasticity deficit, suggesting a role of the MHb-IPN synaptic plasticity in the regulation of aversive behaviors. : The medial habenula-interpeduncular nucleus pathway has been implicated in the regulation of fear and anxiety-like behaviors. Koppensteiner et al. describe a synaptic plasticity mechanism in the medial habenula-interpeduncular nucleus pathway involved in the attenuation of conditioned fear. Keywords: medial habenula, interpeduncular nucleus, glutamate, GABA, GABAB, calcium-permeable AMPA receptors, adolescence, synaptic plasticity, retrograde GABA release, fear extinction