Active intermixing of indirect and direct neurons builds the striatal mosaic

Abstract

The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. While such cellular mosaic ensures the balanced activity of the two pathways, its developmental origin and pattern remains largely unknown. Here, we show that both SPN populations are specified embryonically and intermix progressively through multidirectional iSPN migration. Using conditional mutant mice, we found that inactivation of the dSPN-specific transcription factor Ebf1 impairs selective dSPN properties, including axon pathfinding, while molecular and functional features of iSPN were preserved. Ebf1 mutation disrupted iSPN/dSPN intermixing, resulting in an uneven distribution. Such architectural defect was selective of the matrix compartment, highlighting that intermixing is a parallel process to compartment formation. Our study reveals while iSPN/dSPN specification is largely independent, their intermingling emerges from an active migration of iSPN, thereby providing a novel framework for the building of striatal architecture.

Dynamic postnatal development of the cellular and circuit properties of striatal D1 and D2 spiny projection neurons

“…Moreover, we show that many of the properties of mature D1 and D2 SPNs are already apparent by the first and second postnatal weeks, which is thought to be a period prior to much exploratory motor behaviour (Dehorter et al 2011) or exposure to structured input from the sensory periphery (Tobach et al 1971;Krug et al 2001;Akerman et al 2002;Ko et al 2013;Mowery et al 2015Mowery et al , 2016Mowery et al , 2017. This is consistent with the idea that neuronal specification can occur early in development (Lobo et al 2006(Lobo et al , 2008Arlotta et al 2008;Ehrman et al 2013;Lu et al 2014;Zhang et al 2016;Merchan-Sala et al 2017;Kelly et al 2018;Tinterri et al 2018;Xu et al 2018) with further postnatal development guided by, for example, neural activity (Zhang & Poo, 2001;Kozorovitskiy et al 2012;Peixoto et al 2016) and neuromodulation (Kozorovitskiy et al 2015;Lieberman et al 2018). Future work will be able to clarify the precise interaction of these factors during striatal development as well as their differential involvement in neurodevelopmental disorders (Graybiel & Rauch, 2000;Del Campo et al 2011;Langen et al 2011;McNaught & Mink, 2011;Shepherd, 2013;Albin, 2018).…”

Compartmental function and modulation of the striatum

“…These dopamine islands overlap with immature striosome compartments (Davis & Puhl, 2011;Graybiel, Pickel, Joh, Reis, & Ragsdale, 1981;Hagimoto et al, 2017;Miura, Saino-Saito, Masuda, Kobayashi, & Aosaki, 2007). The homogenous mix of dSPNs and iSPNs observed in adults is this result of a parallel, active intermixing of iSPNs (Tinterri et al, 2018). The homogenous mix of dSPNs and iSPNs observed in adults is this result of a parallel, active intermixing of iSPNs (Tinterri et al, 2018).…”

“…Striatal cells migrate from the lateral ganglionic eminence in two distinct waves, beginning around embryonic days 9.5-13.5 in rodents (Kelly et al, 2018;Tinterri et al, 2018). In fact, striosomes represent some of the oldest and earliest assembled circuit components in the striatum.…”

“…In fact, striosomes represent some of the oldest and earliest assembled circuit components in the striatum. Striatal cells migrate from the lateral ganglionic eminence in two distinct waves, beginning around embryonic days 9.5-13.5 in rodents (Kelly et al, 2018;Tinterri et al, 2018). The cells in the first wave ultimately correspond to striosomal SPNs and migrate to their destinations around the same time as the earliest cortical (Layer 6) neurons do, putting them in position to receive early corticostriatal as well as early thalamostriatal inputs (Fishell & van der Kooy, 1987;…”

“…Once positioned, striosome cells become mostly stationary and cluster together, whereas matrix cells continue to actively migrate in a multidirectional manner during late embryonic development (Hagimoto et al, 2017). The homogenous mix of dSPNs and iSPNs observed in adults is this result of a parallel, active intermixing of iSPNs (Tinterri et al, 2018). While striosomes form a continuous labyrinthine network that extends through the striatum (Graybiel & Ragsdale, 1978), it should be noted that recent work has discovered the presence of scattered SPNs within the matrix (termed "exo-patches") that are more similar to striosome than matrix SPNs in terms of genetic profiles, birth date, synaptic connectivity, and modulation by neuropeptides (Crittenden & Graybiel, 2011;Newman, Liu, & Graybiel, 2015;Smith et al, 2016).…”