Spatial patterning of excitatory and inhibitory neuropil territories during spinal circuit development

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Rhythmic motor behaviors, such as breathing, walking, and swimming, require coordination between excitatory and inhibitory neurotransmission (Goulding, 2009). During the development of spinal circuits, a balance between excitation and inhibition (E/I balance) is achieved even as new neurons exit the cell cycle and integrate into these circuits (Brustein et al., 2003b). Disrupting this E/I balance can result in seizures that are a common symptom in human neurodevelopmental disorders, such as autism, startle disease, and glycine encephalopathy (Eichler & Meier, 2008; Ganser & Dallman, 2009; Harvey, Topf, Harvey, & Rees, 2008; Kozol et al., 2016; Ogino & Hirata, 2016). Previous studies have shown that excitatory and inhibitory synapses often form distinct territories on postsynaptic dendrites (Gulyás, Megías, Emri, & Freund, 1999; Megias, Emri, Freund, & Gulyas, 2001), and that E/I balance can be impacted by the relative distribution of excitatory and inhibitory synapses (Liu, 2004). These studies, however, have focused on dendritic branches of single neurons, while E/I balance is a phenomenon that is observed and maintained not only at the level of individual neurons but also globally at the level of neural circuits (Borodinsky et al., 2004; Knogler, Liao, & Drapeau, 2010). Therefore, to further understand E/I balance in the spinal locomotory circuits, we investigate the distributions of excitatory and inhibitory synapses and processes in the spinal neuropil at the systems level.
In the spinal cord, neuronal somata in the medial cord are flanked by lateral neuropils that are enriched in both excitatory and inhibitory synapses (Tripodi & Arber, 2012). While the types of neurons in spinal circuits are well characterized, the organization of the spinal neuropil has received much less attention. Despite lacking an obvious layering seen in other neuropils like that of the optic tectum (Baier, 2013), previous studies have shown swimming speed and birth order‐related organization of interneuron processes along the medial‐lateral (M‐L) axis of the zebrafish spinal neuropil (McLean & Fetcho, 2009; McLean, Masino, Koh, Lindquist, & Fetcho, 2008; Kinkhabwala et al., 2011). Here, we set out to map excitatory and inhibitory synapses and processes along this spinal neuropil M‐L axis to provide insights into how E/I balance is established and maintained in motor circuits.
The zebrafish (Danio rerio) spinal circuits have some unique characteristics that lend themselves to the study of neural circuit development. These circuits consist of a similar variety of neuron types as those of mammals but have fewer neurons per type (Goulding, 2009), simplifying analysis. These neurons are quite well studied at the level of both physiological connectivity and their role in locomotory behaviors providing critical context for this study (Liao & Fetcho, 2008; McLean & Fetcho, 2009; McLean et al., 2008; Satou et al., 2013). Furthermore, stereotyped rhythmic motor behaviors can be used as direct readouts for E/I balance (Abrams et al., 2015; Brustein et al., 2003b; Burgess & Granato, 2007; Ganser et al., 2013; Kozol et al., 2015). To test whether excitatory and inhibitory synapses and processes form different territories at the systems level, we quantified their distributions in the zebrafish spinal neuropil at two qualitatively distinct developmental stages: 48 hrs postfertilization (hpf), a late embryonic stage characterized by rapid neurogenesis, synaptogenesis, and simple behaviors, and 120 hpf, a larval stage when most neurons are integrated into motor circuits supporting a larger repertoire of rhythmic motor behaviors (Brustein, Marandi, Kovalchuk, Drapeau, & Konnerth, 2003a; Higashijima, Mandel, & Fetcho, 2004).
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