Rapid synaptogenesis in the Nucleus Accumbens is induced by a single cocaine administration and stabilized by MAP Kinase interacting kinase 1 activity

232 words; Text body: 3987 words; Figures : 8 Supplemental Materials include 6 figures and Method s and Materials M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT Dos Santos et al. 2 ABSTRACT Background Repeated cocaine exposure produces new spine format i n in Striatal Projection Neurons (SPNs) of the Nucleus Accumbens (NAc). However, an acute exposure to cocaine can trigger long-lasting synaptic plasticity in SPN leading to behavioral alterations. This raises the intriguing question as to whether acute cocaine cou ld modify enduringly striatal connectivity. Methods A 3D morphometric analysis of presynaptic glutamate rgic boutons and dendritic spines was performed on SPN one hour and one week after a sing le cocaine administration. Time-lapse two-photon microscopy in adult slices was used to d etermine the precise molecular events sequence responsible for the rapid spine formation. Results A single injection triggered a rapid synaptogenesis and persistent increase in glutamatergic connectivity in SPN from the shell part of the NAc, specifically. Synapse formation occurred through clustered growth of active spines contactin g pre-existing axonal boutons. Spine growth required ERK activation, while spine stabili zation involved transcription-independent protein synthesis driven by MAP kinase interacting kinase-1 (MNK-1), downstream from ERK. The maintenance of new spines driven by MNK-1 was essential for long-term connectivity changes induced by cocaine in vivo. Conclusions Our study originally demonstrates that an acute adm inistration of cocaine is able to induce stable synaptic rewiring in the NAc, which will lik ely influence responses to subsequent drug exposure. It also unravels a new functional role fo r c caine-induced ERK pathway M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT Dos Santos et al. 3 independently of nuclear targets. Finally, it revea ls that MNK-1 has a pivotal role in cocaineinduced connectivity.