Abnormalities in inhibitory synaptic transmission are intricately linked to the pathophysiology of psychiatric disorders, but the underlying mechanisms are poorly understood. While synaptic inhibition is crucial throughout the brain, a number of key nodes exist that are particularly heavily controlled by inhibitory inputs, and one of these is the centromedial amygdala (CeM). The CeM represents the major output nucleus of the amygdala complex, through which anxiety responses and other psychiatrically relevant behaviors are processed. CeM neurons receive numerous inhibitory inputs from both afferent projections and local interneurons, which play a pivotal role in gating CeM projections and hence amygdala output. Understanding the biology of these inhibitory synapses is therefore essential in evaluating their vulnerability to pathogenic mutations and their potential as therapeutic targets. In the present study, we investigate the role of two psychiatrically relevant components of the inhibitory postsynapse, the synaptic adhesion molecules Neuroligin 2 (Nlgn2) and IgSF9b, in the CeM anxiety circuitry in mice. Using WT, Nlgn2 KO, IgSF9b KO and double KO mice, we show that deletion of IgSF9b normalizes aberrant anxiety-related behaviors in the open field test and elevated plus maze in Nlgn2 KO mice. This behavioral effect was accompanied by a normalization of neuronal activation in the CeM as assessed using cFos immediate early gene assays and local field potential recordings during exposure to an open field apparatus. To assess the consequences of local deletion of IgSF9b in CeM, we stereotaxically injected AAV-IgSF9b-shRNA under Avertin anaesthesia (20 ml/kg). We show that local knockdown of IgSF9b has prominent anxiolytic consequences in Nlgn2 KO mice. To investigate the mechanism behind the anxiolytic effect of IgSF9b deletion in the CeM, we investigated inhibitory synaptic transmission and inhibitory synapse number in acute slices. We find that deletion of IgSF9b results in increased inhibitory synaptic transmission and an increase in the number of inhibitory synapses in the CeM. These findings support a model in which the anxiety-related CeM overactivation observed in Nlgn2 KO mice is counteracted by the increased inhibition resulting from additional deletion of IgSF9b. Together, our data provide the first description of IgSF9b function in vivo and uncover a novel role for IgSF9b in anxiety-related behavior and amygdala inhibitory synapses. Moreover, our findings highlight that IgSF9b-expressing neurons in the CeM may represent an important common target for anxiolytic treatments that is independent of individual upstream mutations.