Npas4 Regulates Mdm2 and thus Dcx in Experience-Dependent Dendritic Spine Development of Newborn Olfactory Bulb Interneurons

Sensory experience regulates the development of various brain structures, including the cortex, hippocampus, and olfactory bulb (OB). Little is known about how sensory experience regulates the dendritic spine development of OB interneurons, such as granule cells (GCs), although it is well studied in mitral/tufted cells. Here, we identify a transcription factor, Npas4, which is expressed in OB GCs immediately after sensory input and is required for dendritic spine formation. Npas4 overexpression in OB GCs increases dendritic spine density, even under sensory deprivation, and rescues reduction of dendrite spine density in the Npas4 knockout OB. Furthermore, loss of Npas4 upregulates expression of the E3-ubiquitin ligase Mdm2, which ubiquitinates a microtubule-associated protein Dcx. This leads to reduction in the dendritic spine density of OB GCs. Together, these findings suggest that Npas4 regulates Mdm2 expression to ubiquitinate and degrade Dcx during dendritic spine development in newborn OB GCs after sensory experience. [Display omitted] •Npas4 regulates dendritic spine development in newborn olfactory bulb (OB) neurons•Npas4 overexpression rescues reduction of spine density in Npas4-KO OB neurons•Loss of Npas4 upregulates expression of the E3 ubiquitin ligase Mdm2•Mdm2 ubiquitinates and degrades Dcx to reduce the spine density of OB neurons Although sensory experience is known to regulate the development of various brain structures, including the cortex, hippocampus, and olfactory bulb (OB), how it controls the dendritic spine development of OB interneurons such as granule cells (GCs) remains unknown. Yoshihara et al. reveal that a transcription factor Npas4, expressed in OB GCs immediately after sensory input, represses expression of an E3-ubiquitin ligase, Mdm2, that targets the microtubule-associated protein Dcx, resulting in increased dendritic spine development in newborn GCs.