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

Abstract

Key points Imbalances in the activity of the D1‐expressing direct pathway and D2‐expressing indirect pathway striatal projection neurons (SPNs) are thought to contribute to many basal ganglia disorders, including early‐onset neurodevelopmental disorders such as obsessive–compulsive disorder, attention deficit hyperactivity disorder and Tourette's syndrome. This study provides the first detailed quantitative investigation of development of D1 and D2 SPNs, including their cellular properties and connectivity within neural circuits, during the first postnatal weeks. This period is highly dynamic with many properties changing, but it is possible to make three main observations: many aspects of D1 and D2 SPNs progressively mature in parallel; there are notable exceptions when they diverge; and many of the defining properties of mature striatal SPNs and circuits are already established by the first and second postnatal weeks, suggesting guidance through intrinsic developmental programmes. These findings provide an experimental framework for future studies of striatal development in both health and disease. Abstract Many basal ganglia neurodevelopmental disorders are thought to result from imbalances in the activity of the D1‐expressing direct pathway and D2‐expressing indirect pathway striatal projection neurons (SPNs). Insight into these disorders is reliant on our understanding of normal D1 and D2 SPN development. Here we provide the first detailed study and quantification of the striatal cellular and circuit changes occurring for both D1 and D2 SPNs in the first postnatal weeks using in vitro whole‐cell patch‐clamp electrophysiology. Characterization of their intrinsic electrophysiological and morphological properties, the excitatory long‐range inputs coming from cortex and thalamus, as well their local gap junction and inhibitory synaptic connections reveals this period to be highly dynamic with numerous properties changing. However it is possible to make three main observations. Firstly, many aspects of SPNs mature in parallel, including intrinsic membrane properties, increases in dendritic arbours and spine densities, general synaptic inputs and expression of specific glutamate receptors. Secondly, there are notable exceptions, including a transient stronger thalamic innervation of D2 SPNs and stronger cortical NMDA receptor‐mediated inputs to D1 SPNs, both in the second postnatal week. Thirdly, many of the defining properties of mature D1 and D2 SPNs and striatal circuits are already established by the first and second postnatal weeks, including different electrophysiological properties as well as biased local inhibitory connections between SPNs, suggesting this is guided through intrinsic developmental programmes. Together these findings provide an experimental framework for future studies of D1 and D2 SPN development in health and disease.

Striatal Circuit Development and Its Alterations in Huntington’s Disease

“…Regarding morphology, this maturation involves the development of the dendritic arbor and the formation of dendritic spines, with their density increasing gradually especially between PND10 and PND12 ( Figure 2B-C). SPN activity also increases from P10, with an overall increase in spontaneous firing rate and burst frequency observed ex vivo (Krajeski et al, 2019;Peixoto et al, 2016). Conversely, the intrinsic excitability of SPNs progressively decreases caused by an hyperpolarization of their resting membrane potential and a longer latency to spike firing (higher rheobase and action potential threshold seen ex vivo) (Dehorter et al, 2011;Krajeski et al, 2019;Peixoto et al, 2016).…”

“…Regarding SPN morphology and excitability, it has been shown that during the first postnatal week, neonatal SPNs express immature characteristics as indicated by an absence or slight presence of dendritic spines as well as the presence of thin and varicose dendrites ( Figure 2B-C) (Sharpe and Tepper, 1998). In terms of their electrophysiological properties, SPNs exhibit immature patterns of activity compared to the adult state, with a lower level of spontaneous activity in vivo, and an hyperexcitability observed both in vivo and ex vivo (Dehorter et al, 2011;Krajeski et al, 2019;Tepper and Trent, 1993). This elevated intrinsic excitability of immature neurons during development, which found in many brain structures and across many species, has been shown to be crucial to developmental processes such as neuronal growth and synapse formation (Spitzer, 2006).…”

“…Dopamine release was shown to be crucial for the maturation of dSPNs as the lack of nigrostriatal dopaminergic transmission prevents the decrease in dSPNs excitability (Lieberman et al, 2018). In parallel, cortical neurons send their axonal projections to the striatum from PND3 (Sohur et al, 2014) but only 75% of SPNs respond to cortical stimulation between PND3 and PND6, indicative of ongoing corticostriatal synaptogenesis (Krajeski et al, 2019). From PND9, all SPNs receive cortical innervation and these excitatory inputs continue to develop progressively, especially between PND10 and PND18 suggesting an ongoing strengthening of corticostriatal synapses (Figure 2B-C) (Krajeski et al, 2019;Peixoto et al, 2016).…”

“…In parallel, cortical neurons send their axonal projections to the striatum from PND3 (Sohur et al, 2014) but only 75% of SPNs respond to cortical stimulation between PND3 and PND6, indicative of ongoing corticostriatal synaptogenesis (Krajeski et al, 2019). From PND9, all SPNs receive cortical innervation and these excitatory inputs continue to develop progressively, especially between PND10 and PND18 suggesting an ongoing strengthening of corticostriatal synapses (Figure 2B-C) (Krajeski et al, 2019;Peixoto et al, 2016). Cortex and striatum development appear to be strongly interdependent as an alteration in either striatal or cortical activity during this period has a strong impact on corticostriatal connectivity (Kozorovitskiy et al, 2012;Peixoto et al, 2016).…”

“…Finally, thalamic neurons send their projections from at least by PND3 as 75% of SPNs respond to a thalamic stimulation at this stage, but the establishment of thalamo-striatal synapses could start even earlier as VGLUT2-positive axons are already found at birth in the striatum (Nakamura et al, 2005). Similarly to the cortical inputs, all SPNs receive thalamic inputs from PND9 and the amplitude of these inputs increase progressively until PND28, also suggesting a continued strengthening of thalamostriatal synapses (Krajeski et al, 2019). As described earlier, striosomal and matrix striatogenesis occur sequentially, with an early production and migration of striosomal SPNs followed by matrix ones (see § II.1.).…”