Journal
JOURNAL OF NEUROSCIENCE
Volume 41, Issue 39, Pages 8111-8125Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0352-21.2021
Keywords
dendrite; development; dysplasia; kinase; synapse assembly; synapse maturation
Categories
Funding
- Deutsche Forschungsgemeinschaft [SFB 1089, FOR2715, SCHO 820/4-1, SCHO 820/6-1, SCHO 820/7-1, SCHO 820/5-2, SPP1757]
- University of Bonn Medical Center BONFOR program
- DeCipher EraNet Neuron BMBF [01EW1606]
- Else Kroner-Fresenius Foundation EKFS-Promotionskolleg NeuroImmunology
- BMBF [01GQ0806]
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SLK plays a critical role in the development of cortical neurons in mice, specifically in the elaboration of higher dendrites and maintaining the balance between excitation and inhibition. Knockdown of SLK leads to loss of inhibitory synapses and functional inhibition in mouse neurons, with potential relevance to human cortical malformations.
The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output. The regulatory mechanisms governing the development of dendrites, however, are insufficiently understood. The evolutionary conserved Ste20/Hippo kinase pathway has been proposed to play an important role in regulating the formation and maintenance of dendritic architecture. A key element of this pathway, Ste20-like kinase (SLK), regulates cytoskeletal dynamics in non-neuronal cells and is strongly expressed throughout neuronal development. However, its function in neurons is unknown. We show that, during development of mouse cortical neurons, SLK has a surprisingly specific role for proper elaboration of higher, >= third-order dendrites both in male and in female mice. Moreover, we demonstrate that SLK is required to maintain excitation-inhibition balance. Specifically, SLK knockdown caused a selective loss of inhibitory synapses and functional inhibition after postnatal day 15, whereas excitatory neurotransmission was unaffected. Finally, we show that this mechanism may be relevant for human disease, as dysmorphic neurons within human cortical malformations revealed significant loss of SLK expression. Overall, the present data identify SLK as a key regulator of both dendritic complexity during development and inhibitory synapse maintenance.
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