Abstract: There is a strong evidence supporting the hypothesis of synaptic dysfunction as a major contributor to neural circuit and network disruption underlying emotional and mood dysregulation in psychiatric disorders (Simmons et al., 2024). Diverse sets of distinct molecular signaling pathways converge on the synapse to regulate synaptogenesis, synaptic function, and synaptic plasticity in brain regions and circuits through complex interactions organized by numerous multivalent protein scaffolds, including the family of proteins known as A-kinase anchoring proteins (AKAPs). Extensive and ongoing research into molecular mechanisms regulating synaptic function and plasticity in memory-related brain circuits has highlighted the significance of a member of the AKAP family, namely AKAP5 (AKAP79 human/AKAP150 rodent/Akap5 gene), in cognitive and memory processes (Wild and Dell’Acqua, 2018). For simplicity, we use AKAP5 for AKAP79/150 throughout the review but specify AKAP150 in rodent studies discussed here. Emerging evidence also points out the potential role of AKAP5 in the development of depressive phenotypes (Corcoran et al., 2015; Guercio et al., 2018; Bai et al., 2023; Simmons et al., 2024; Wang et al., 2024) and the rapid-acting antidepressant effects of ketamine (Lopez et al., 2022). Yet our understanding of the potential dysregulation of AKAP5 signaling complexes in the promotion of specific synaptic abnormalities in neural circuits involved in mood disorders remains elusive. This is a significant gap in knowledge as human genetic studies strongly indicate that AKAP5 gene polymorphisms/mutations may play a role in the etiology of psychiatric illnesses such as schizophrenia, bipolar disorder, and depression (Simmons et al., 2024). The primary goal of this perspective is to briefly discuss a few recent developments in our understanding of AKAP5- related regulation of synaptic, neuronal excitability, and stress neuromodulation within brain reward circuits in the context of mood- and addictionrelated behaviors (Figure 1). We highlight some of the less explored aspects of AKAP signaling where AKAP5 is perfectly situated to serve as a molecular bridge integrating signals from multiple molecular pathways to specifically and efficiently regulate synaptic transmission and plasticity, and neuronal excitability vital for shaping neural circuits and networks underlying our behavior. We then conclude with a brief discussion of how a lack of well-organized AKAP5 signaling leads to synaptic dysfunction within the stress and reward-related brain regions, underscoring the therapeutic potential of drugs that target the AKAP5 protein– protein interactions in the treatment of psychiatric illnesses and substance use disorders. We further propose outstanding questions to be addressed in future research by leveraging technological advances in neuroscience and drug development to better understand the role of AKAP5 in the regulation of stress, motivation, and mood, and for AKAP5-targeted therapies using the emerging precision pharmacology and medicine in treatment of neurological and neuropsychiatric illnesses.