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The predisposition of Autism Spectrum Disorder (ASD) to Post-Traumatic Stress Disorder (PTSD) remained to be established. Here, we show that exposure to a single mild stressful event induces maladaptive memory, which recapitulates all features of PTSD, and is associated with the broad dysfunction of the prefrontal-hippocampo-amygdalar network. Using optogenetics, we demonstrate that prefrontal cortex hyperactivation triggers this PTSD-like memory. Finally, we show that recontextualization of the traumatic event normalizes maladaptive memory in ASD conditions. Overall, this study provides the first direct demonstration that ASD represents a risk factor for PTSD and uncovers new mechanisms that underlie pathological memory formation.

International audience; The aim of the present experiment was to directly assess the role of the glutamatergic hippocampal-lateral septal (HPC-LS) neurotransmission in tone and contextual fear conditioning. We found that pretraining infusion of glutamatergic acid into the lateral septum promotes tone conditioning and concomitantly disrupts contextual conditioning. Infusion of glutamatergic antagonist, on the contrary, promotes contextual conditioning to the detriment of tone fear conditioning. These findings highlight the direct contribution of the glutamatergic HPC-LS neurotransmission to the adaptive selection among environmental stimuli of those that best predict the occurrence of the aversive event.

Extensive evidence indicates that the septum plays a predominant role in fear learning, yet the direction of this control is still a matter of debate. Increasing data suggest that the medial (MS) and lateral septum (LS) would be differentially required in fear conditioning depending on whether a discrete conditional stimulus (CS) predicts, or not, the occurrence of an aversive unconditional stimulus (US). Here, using a tone CS-US pairing (predictive discrete CS, context in background) or unpairing (context in foreground) conditioning procedure, we show, in mice, that pretraining inactivation of the LS totally disrupted tone fear conditioning, which, otherwise, was spared by inactivation of the MS. Inactivating the LS also reduced foreground contextual fear conditioning, while sparing the higher level of conditioned freezing to the foreground (CS-US unpairing) than to the background context (CS-US pairing). In contrast, inactivation of the MS totally abolished this training-dependent level of contextual freezing. Interestingly, inactivation of the MS enhanced background contextual conditioning under the pairing condition, whereas it reduced foreground contextual conditioning under the unpairing condition. Hence, the present findings reveal a functional dissociation between the LS and the MS in Pavlovian fear conditioning depending on the predictive value of the discrete CS. While the requirement of the LS is crucial for the appropriate processing of the tone CS-US association, the MS is crucial for an appropriate processing of contextual cues as foreground or background information.