Disengagement of Somatostatin Neurons From Lateral Septum Circuitry by Oxytocin and Vasopressin Restores Social Fear Extinction and Suppresses Aggression Outbursts in a Prader-Willi Syndrome Model

Abstract

Listen

Translate article

BackgroundResponding to social signals by expressing the correct behavior is not only challenged in autism but also in diseases with a high prevalence of autism, such as Prader-Willi syndrome. Clinical evidence suggests that aberrant prosocial behavior in patients can be regulated by intranasal oxytocin (OXT) or vasopressin (AVP). However, the neuronal mechanisms that underlie impaired behavioral responses in a socially aversive context, and how can they be corrected, remain largely unknown. MethodsUsing the Magel2 knockout mouse model of Prader-Willi syndrome (crossed with CRE-dependent transgenic lines), we devised optogenetic, physiological, and pharmacological strategies in a social fear conditioning paradigm. Pathway-specific roles of OXT and AVP signaling were investigated converging on the lateral septum (LS), a region that receives dense hypothalamic inputs. ResultsOXT and AVP signaling promoted inhibitory synaptic transmission in the LS, the failure of which in Magel2 knockout mice disinhibited somatostatin (SST) neurons and disrupted social fear extinction. The source of OXT and AVP deficits mapped specifically in the supraoptic nucleus→LS pathway of Magel2 knockout mice with disrupted social fear extinction, which could be corrected by optogenetic or pharmacological inhibition of SST neurons in the LS. Interestingly, LS SST neurons also gated the expression of aggressive behavior, possibly as part of functional units that operate beyond local septal circuits. ConclusionsSST cells in the LS play a crucial role in integration and expression of disrupted neuropeptide signals in autism, thereby altering the balance in expression of safety versus fear. Our results uncover novel mechanisms underlying dysfunction in a socially aversive context and provide a new framework for future treatments for autism spectrum disorder.