Retinal Input Directs the Recruitment of Inhibitory Interneurons into Thalamic Visual Circuits

Abstract

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.

Tectal-derived interneurons contribute to phasic and tonic inhibition in the visual thalamus

“…Furthermore, reciprocal repression between Dlx1/2 and Gata2/3 suggests that alternative GABA fates are acquired in p3 and pTh-R (refs 17, 18, 19). A recent report described an Otx2 -positive and Sox14 -negative GABAergic lineage in p3 that contributes to local thalamic interneurons25, providing experimental support to the prevailing hypothesis that dLGN interneurons have a prethalamic origin2627. In contrast, in this study we report that p3, as well as pTh-R and p1, are unlikely sources of thalamic interneurons and propose an alternative model whereby an incoming tectal population seeds the thalamus with inhibitory interneurons in a process requiring Gata2 and Sox14 .…”

“…We and others have reported that the Sox14 gene is often associated with GABAergic neurons in subcortical brain regions1517192223, but this association was thought not to apply for local thalamic interneurons25. The observation of scattered Gfp + cells within thalamic relay nuclei of Sox14 Gfp/+ mice was therefore, unexpected.…”

“…17), and its ablation results in Sox14 Gfp/Gfp ( Sox14 knockout) embryos having a much-reduced number of Gfp + neurons in the ventral LGN (vLGN) at the time of birth17. Because dLGN-INs are known to migrate into the nucleus postnatally2526, we extended our previous analysis17 of the Sox14 knockout thalamus to the postnatal brain (Fig. 2a).…”

Stochastic Interaction between Neural Activity and Molecular Cues in the Formation of Topographic Maps

“…Here, we show that retinal waves can play an instructional role in the local organization of the retinocollicular map, resulting in dramatic rearrangements distinct from those predicted by the local relative signaling and permissive arborization models previously proposed. The instructive nature of these waves has previously been demonstrated for the alignment of visual topographic maps of space in the SC (Triplett et al, 2009) and the migration of interneurons in the dorsal lateral geniculate nucleus (Golding et al, 2014). However, the specific mechanisms by which these waves are able to mediate such instruction remain unclear.…”

An evolving view of retinogeniculate transmission

“…Many of the modulatory circuits that shape transmission in the adult dLGN begin to innervate TC neurons shortly before eye-opening: corticogeniculate innervation is not complete in mice until p14 (Jacobs et al, 2007; Seabrook et al, 2013; Grant et al, 2016), and cholinergic innervation develops over several postnatal weeks in cats (Carden et al, 2000). GABAergic interneurons continue to be recruited into the dLGN at the end of the first postnatal week in mice, and GABAergic innervation in rodents and carnivores occurs gradually (Shatz and Kirkwood, 1984; Ramoa & McCormick, 1994a; Pirchio et al, 1997; Ziburkus et al, 2003; Golding et al, 2014). In addition, presynaptic ultrastructural morphology and TC dendritic arbor complexity are immature at eye-opening (Bickford et al, 2010).…”