LUZP1 Regulates Dendritic Spine Maturation and Synaptic Plasticity in the Hippocampal Dentate Gyrus of Mice

Leucine zipper protein 1 (LUZP1) functions in the maintenance and dynamics of the cytoskeleton by interacting with actin and microtubules. Deficiency or mutation of LUZP1 is associated with brain developmental disorders, however, its precise role in brain function remains unclear. We showed that LUZP1 localizes to actin and is highly expressed in CaMKIIα-expressing neurons within the mouse hippocampal dentate gyrus. Depletion of LUZP1 impedes dendritic spine maturation, which is characterized by excess immature filopodia and loss of mature mushroom spines both in vitro and in vivo. LUZP1 knockdown reduces spontaneous electrical activity and synaptic plasticity in hippocampal neurons. Conditional deletion of LUZP1 in CaMKIIα-expressing neurons causes impaired learning and memory behavior in mice of both sexes. Mechanistically, LUZP1 control dendritic maturation by directly interacting with filamin A and modulating the Rac1-PAK1 signaling pathway. These findings shed light on the role of LUZP1 in regulating synaptic plasticity and brain function. Significance Statement Unraveling brain development and function is critical for understanding neurological disorders. The discovery of LUZP1 sheds light on cytoskeletal dynamics, crucial for brain health. LUZP1's interaction with actin and its link to brain disorders highlight its neural importance. LUZP1's presence in specific hippocampal neurons, notably CaMKIIα-expressing ones, provides insights into synaptic function. Depletion of LUZP1 hinders dendritic spine maturation, impacting synaptic activity and plasticity, crucial for neural connectivity. The association of LUZP1 with learning impairments upon deletion in neurons emphasizes its role in cognition. Its involvement in the Rac1-PAK1 pathway offers novel insights into dendritic maturation and synaptic plasticity regulation. These discoveries illuminate LUZP1's significant impact on synaptic plasticity and brain function, hinting at potential interventions for LUZP1-associated neurological disorders.