Search

Neurons of the CNS elaborate highly branched dendritic arbors that host numerous dendritic spines, which serve as the postsynaptic platform for most excitatory synapses. The actin cytoskeleton plays an important role in dendrite development and spine formation, but the underlying mechanisms remain incompletely understood. Tropomodulins (Tmods) are a family of actin-binding proteins that cap the slow-growing (pointed) end of actin filaments, thereby regulating the stability, length, and architecture of complex actin networks in diverse cell types. Three members of the Tmod family, Tmod1, Tmod2, and Tmod3 are expressed in the vertebrate CNS, but their function in neuronal development is largely unknown. In this study, we present evidence that Tmod1 and Tmod2 exhibit distinct roles in regulating spine development and dendritic arborization, respectively. Using rat hippocampal tissues from both sexes, we find that Tmod1 and Tmod2 are expressed with distinct developmental profiles: Tmod2 is expressed early during hippocampal development, whereas Tmod1 expression coincides with synaptogenesis. We then show that knockdown of Tmod2, but not Tmod1, severely impairs dendritic branching. Both Tmod1 and Tmod2 are localized to a distinct subspine region where they regulate local F-actin stability. However, the knockdown of Tmod1, but not Tmod2, disrupts spine morphogenesis and impairs synapse formation. Collectively, these findings demonstrate that regulation of the actin cytoskeleton by different members of the Tmod family plays an important role in distinct aspects of dendrite and spine development.SIGNIFICANCE STATEMENTThe Tropomodulin family of molecules is best known for controlling the length and stability of actin myofilaments in skeletal muscles. While several Tropomodulin members are expressed in the brain, fundamental knowledge about their role in neuronal function is limited. In this study, we show the unique expression profile and subcellular distribution of Tmod1 and Tmod2 in hippocampal neurons. While both Tmod1 and Tmod2 regulate F-actin stability, we find that they exhibit isoform-specific roles in dendrite development and synapse formation: Tmod2 regulates dendritic arborization, whereas Tmod1 is required for spine development and synapse formation. These findings provide novel insight into the actin regulatory mechanisms underlying neuronal development, thereby shedding light on potential pathways disrupted in a number of neurological disorders.

Katalin Schlett previews the study by Lei et al., which reveals that dendritic spines contain local pools of G-actin that are dynamically regulated in response to synaptic activity by profilin and PIP3., Synaptic activity reshapes the morphology of dendritic spines via regulating F-actin arborization. In this issue, Lei et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201612042) reports a novel, G-actin–dependent regulation of actin polymerization within spine heads. They show that actin monomer levels are elevated in spines upon activity, with G-actin immobilized by the local enrichment of phosphatidylinositol (3,4,5)-triphosphate (PIP3) within the spine plasma membrane.

Two distinct protein cofactors, p35 and p39, independently activate Cyclin-dependent kinase 5 (Cdk5), which plays diverse roles in normal brain function and the pathogenesis of many neurological diseases. The initial discovery that loss of p35 impairs neuronal migration in the embryonic brain prompted intensive research exploring the function of p35-dependent Cdk5 activity. In contrast, p39 expression is restricted to the postnatal brain and its function remains poorly understood. Despite the robustly increased Cdk5 activity during neuronal differentiation, which activator is responsible for enhancing Cdk5 activation and how the two distinct activators direct Cdk5 signaling to govern neuronal network formation and function still remains elusive. Here we report that p39, but not p35, is selectively upregulated by histone acetylation-mediated transcription, which underlies the robust increase of Cdk5 activity during rat and mouse neuronal differentiation. The loss of p39 attenuates overall Cdk5 activity in neurons and preferentially affects phosphorylation of specific Cdk5 targets, leading to aberrant axonal growth and impaired dendritic spine and synapse formation. In adult mouse brains, p39 deficiency results in dysregulation of p35 and Cdk5 targets in synapses. Moreover, in contrast to the proepileptic phenotype caused by the lack of p35, p39 loss leads to deficits in maintaining seizure activity and induction of immediate early genes that control hippocampal excitability. Together, our studies demonstrate essential roles of p39 in neuronal network development and function. Furthermore, our data support a model in which Cdk5 activators play nonoverlapping and even opposing roles to govern balanced Cdk5 signaling in the postnatal brain.SIGNIFICANCE STATEMENTNeuronal network development requires tightly regulated activation of Cyclin-dependent kinase 5 (Cdk5) by two distinct cofactors, p35 and p39. Despite the well-known p35-dependent Cdk5 function, why postnatal neurons express abundant p39 in addition to p35 remained unknown for decades. In this study, we discovered that selective upregulation of p39 is the underlying mechanism that accommodates the increased functional requirement of Cdk5 activation during neuronal differentiation. In addition, we demonstrated that p39 selectively directs Cdk5 to phosphorylate protein substrates essential for axonal development, dendritic spine formation, and synaptogenesis. Moreover, our studies suggest opposing roles of p39 and p35 in synaptic Cdk5 function and epileptic responses, arguing that cooperation between Cdk5 activators maintains balanced Cdk5 signing, which is crucial for postnatal brain function.

Background Synaptic defects represent a major mechanism underlying altered brain functions of patients suffering Alzheimer's disease (AD) [1–3]. An increasing body of work indicates that the oligomeric forms of β-amyloid (Aβ) molecules exert profound inhibition on synaptic functions and can cause a significant loss of neurotransmitter receptors from the postsynaptic surface, but the underlying mechanisms remain poorly understood. In this study, we investigated a potential contribution of mitochondria to Aβ inhibition of AMPA receptor (AMPAR) trafficking. Results We found that a brief exposure of hippocampal neurons to Aβ oligomers not only led to marked removal of AMPARs from postsynaptic surface but also impaired rapid AMPAR insertion during chemically-induced synaptic potentiation. We also found that Aβ oligomers exerted acute impairment of fast mitochondrial transport, as well as mitochondrial translocation into dendritic spines in response to repetitive membrane depolarization. Quantitative analyses at the single spine level showed a positive correlation between spine-mitochondria association and the surface accumulation of AMPARs. In particular, we found that spines associated with mitochondria tended to be more resistant to Aβ inhibition on AMPAR trafficking. Finally, we showed that inhibition of GSK3β alleviated Aβ impairment of mitochondrial transport, and effectively abolished Aβ-induced AMPAR loss and inhibition of AMPAR insertion at spines during cLTP. Conclusions Our findings indicate that mitochondrial association with dendritic spines may play an important role in supporting AMPAR presence on or trafficking to the postsynaptic membrane. Aβ disruption of mitochondrial trafficking could contribute to AMPAR removal and trafficking defects leading to synaptic inhibition.