Abstract
Dendritic spine development is crucial for the establishment of excitatory synaptic connectivity and functional neural circuits. Alterations in spine morphology and density have been associated with multiple neurological disorders. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. However, the role of DIP2A in the brain remains largely unknown. In this study, we found that deletion of Dip2a in mice induced defects in spine morphogenesis along with thin postsynaptic density (PSD), and reduced synaptic transmission of pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin. Furthermore, Dip2a knockout (KO) mice exhibited autism-like behaviors, including excessive repetitive behaviors and defects in social novelty. Importantly, acetylation mimetic cortactin restored the impaired synaptic transmission and ameliorated repetitive behaviors in these mice. Altogether, our findings establish an initial link between DIP2A gene variations in autism spectrum disorder (ASD) and highlight the contribution of synaptic protein acetylation to synaptic processing.
Highlights
Dendritic spines are small protrusions that represent the postsynaptic component of most excitatory synapses
The subcellular localization of disconnected-interacting protein homolog 2 A (DIP2A) exhibited that it clustered at dendritic shafts and spines at day 18 in vitro (DIV18) of cultured neurons and partially colocalized with the postsynaptic marker, PSD95 (Fig 1D)
DIP2A regulates spine morphogenesis via ac-cortactin together, these results suggest DIP2A is preferentially expressed in excitatory neurons and prompt us to investigate its function in the synaptic compartment
Summary
Dendritic spines are small protrusions that represent the postsynaptic component of most excitatory synapses. Changes in spine shape and density have been considered as a hallmark of synaptic plasticity, which is associated with learning, aging, and neurodevelopmental disorders [1,2,3]. Synaptic plasticity is dependent on the actin dynamics in dendritic spines [4,5,6]. Cortactin is an important regulator of actin nucleation that has been shown to impact spine. DIP2A regulates spine morphogenesis via ac-cortactin of the Science Foundation of Jilin Province (20180414046GH to ZH, http://kjt.jl.gov.cn/), and the Fundamental Research Funds for the Central Universities (2412018JC010 to ZH, 2019005 to XZ, http://kjt.jl.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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