Abstract
Structural changes in pre and postsynaptic neurons that accompany synapse formation often temporally and spatially overlap. Thus, it has been difficult to resolve which processes drive patterned connectivity. To overcome this, we use the laminated outer murine retina. We identify the serine/threonine kinase LKB1 as a key driver of synapse layer emergence. The absence of LKB1 in the retina caused a marked mislocalization and delay in synapse layer formation. In parallel, LKB1 modulated postsynaptic horizontal cell refinement and presynaptic photoreceptor axon growth. Mislocalized horizontal cell processes contacted aberrant cone axons in LKB1 mutants. These defects coincided with altered synapse protein organization, and horizontal cell neurites were misdirected to ectopic synapse protein regions. Together, these data suggest that LKB1 instructs the timing and location of connectivity in the outer retina via coordinate regulation of pre and postsynaptic neuron structure and the localization of synapse-associated proteins.
Highlights
The precise spatial and temporal regulation of neuron maturation and synapse formation is crucial to ensure the fidelity of neural circuits
In control animals the nascent outer plexiform layer (OPL) first appears as small discontinuous patches at postnatal day 3 (P3), where horizontal cell neurites and cone terminals begin to form contacts
We used VGLUT1 staining as a readout for synapse protein mislocalization since it was the only protein we identified that was present at high levels during OPL emergence (P3-P5)
Summary
The precise spatial and temporal regulation of neuron maturation and synapse formation is crucial to ensure the fidelity of neural circuits. We know little about how these processes contribute to the emergence of ordered connectivity In part, this is because many neurons form a large number of synapses, and these synapses are broadly distributed along the neuron. This is because many neurons form a large number of synapses, and these synapses are broadly distributed along the neuron This makes it difficult to resolve the cellular and molecular drivers of these events. To solve this problem, we use the outer retina since it is one of the few regions in the mammalian central nervous system (CNS) where neuronal cell types and their basic connectivity are known (Sanes and Zipursky, 2010; Behrens et al, 2016; Shekhar et al, 2016). Because each photoreceptor forms connections at one large distal location, the relationship between the structure and maturation of both pre and postsynaptic neurons relative to their connectivity can be directly examined
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