Deletion of NRXN1α impairs long-range and local connectivity in amygdala fear circuit

Abstract

Neurexins are a family of presynaptic cell adhesion proteins that regulate synaptic structure and maintain normal synaptic transmission. Mutations in the α-isoform of neurexin1-gene (NRXN1α) are linked with cognitive and emotional dysregulation, which are heavily dependent on the amygdala and medial prefrontal cortex (mPFC). It is however not known whether deletion of NRXN1α gene affect specific synaptic elements within the amygdala microcircuit and connectivity with mPFC. In this study, we show that NRXN1α deletion impairs synaptic transmission between the dorsal medial prefrontal cortex (dmPFC) and basal amygdala (BA) principal neurons. Stimulation of dmPFC fibers resulted in reduced paired pulse ratio (PPR) and AMPA/NMDA ratio at dmPFC to BA synapses in NRXN1α-knockout (KO) (NRXN1α KO) mice suggestive of pre- and postsynaptic deficits but there was no change at the lateral amygdala (LA) to BA synapses following LA stimulation. However, feedforward inhibition from either pathway was significantly reduced, suggestive of input-independent deficit in GABAergic transmission within BA. We further analyzed BA inhibitory network and found reduced connectivity between BA GABAergic and glutamatergic neurons in NRXN1α KO mice. As this circuit is tightly linked with fear regulation, we subjected NRXN1α KO and WT mice to discriminative fear conditioning and found a deficit in fear memory retrieval in NRXN1α KO mice compared with WT mice. Together, we provide novel evidence that deletion of NRNX1α disrupts amygdala fear circuit.