Neuronal studies have provided insight into the mechanisms of some missense mutations, particularly within the GEF domains of KALRN. A mutation found within the Rac-GEF domain was found to induce strong reductions in Rac activation, neuronal branching and spine density. These effects were mirrored by mutations in the RhoA-GEF domain, producing similar neuronal deficits, but by promoting RhoA-GEF activity. In addition to exome sequencing, post-mortem studies have consistently found alterations in kalirin transcript levels within the brain further supporting a role for kalirin in the etiology of schizophrenia. In addition to neurodevelopmental disorders, kalirin has been found to be underexpressed in the post-mortem Alzheimer’s brain. This loss of kalirin expression was recapitulated in animal models of Alzheimer’s disease. Moreover, introduction of kalirin7 into culture or animal models of Alzheimer’s disease was able to rescue synaptic and behavioral deficits, suggesting an important role for kalirin in regulating synapse loss and cognitive impairment in Alzheimer’s disease. Function The majority of kalirin’s effects are induced through its catalytic GEF domain signaling. By promoting the release of GDP from Rac and RhoA , it acts as an activator of GTPase signaling within the cell. Although able to activate Rac and RhoA, much of its activity in regulating neuronal morphology has been attributed to Rac-PAK pathway activation. kalirin has found been found to exert control over dendritic arborization, axonal growth, dendritic spine formation and synaptic activity and plasticity. These effects are regulated by protein-protein interactions and post-translational modifications within the non-catalytic domains, and have been shown to exert control over kalirin subcellular targeting and activation. Kalirin has been found to play a critical role in synaptic activity and plasticity. Loss of KALRN results in decreased nMDAr and AMPAr-mediated mEPSC, and kalirin7 knockout animals show strong deficits in NMDAr mediated long term potentiation and long term depression. This may be linked to the ability to regulate RAC-PAK signaling and actin dynamics, which in turn can regulate the size and density of dendritic spines. Within dendritic spines, kalirin interacts with multiple disease related proteins to regulate synapse strength. It directly interacts with the schizophrenia risk factor DISC1 that can act to suppress kalirin function within the spine. Furthermore, kalirin7 directly interacts with the GluN2B subunit of the NMDA receptor and PSD95 within the post-synaptic density. The importance of KALRN in neurodevelopment is supported by knockout animal models that display profound deficiencies in multiple behavioral tasks. Kalirin knockout