|Spine density on the basilar dendrites of pyramidal neurons is lower in layer 3, but not in layers 5-6, in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia. The expression of CDC42, which promotes spine formation, is also lower in thse subjects; however, the deficit in CDC42 mRNA is present across layers 3-6, suggesting that other lamina-specific molecular alterations are critical for the appearance of the spine deficits in the illness. The CDC42 effector protein 3 (CDC42EP3) is preferentially expressed in human DLPFC layers 2 and 3, and appears to assemble septin filaments in spine necks. We found that the expression of CDC42EP3 mRNA was significantly increased by 19.7%, and SEPT7 mRNA was significantly decreased by 6.9% in subjects with schizophrenia. These findings suggest the following model (panel) for spine dysfunction in schizophrenia. (A) CDC42EP3 binds to septins via its BD3 domain, inducing the assembly of septin filaments. The inactive form of CDC42 cannot bind to the CRIB domain of CDC42EP3. (B) The activated form of CDC42 binds to CDC42EP3 via its CRIB domain and inhibits CDC42EP3, disrupting the septin filament assembly. (C top) In the normal state, CDC42EP3 consolidates the septin 5/7/11 complex in spine necks, providing a barrier for molecular diffusion with the parent dendrite. (C middle) Transient activation of CDC42 by glutamate stimulation inhibits the CDC42EP3-mediated assembly of the septin barrier (C bottom) enabling postsynaptic molecules to enter the spine for synaptic potentiation. (D top) In schizophrenia, decreased mRNA expression of SEPT7 contributes to an impaired septin barrier function at the spine neck, limiting the retention of postsynaptic molecules, such as cytoskeletal proteins and/or second messengers, which are critical for spine structure and function in the spine head. (D middle) Furthermore, lower levels of CDC42 and increased levels of CDC42EP3 lead to a reduced capacity for glutamatergic stimuli to produce opening of the septin barrier, impairing synaptic plasticity and contributing to spine loss (D bottom).