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. 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.
Highlights
The striatum is the main input nucleus of the basal ganglia and consists of two populations of projection neurons with distinct long-range outputs, the D2 SPN at P9–12 (D1)-expressing direct pathway spiny projection neurons (SPNs) and the D2-expressing indirect pathway SPNs (Day et al 2008; Gertler et al 2008), which differentially regulate motor behaviour and cognitive function (Graybiel et al 1994; Grillner et al 2005; Yin & Knowlton, 2006; Kravitz et al 2010; Tecuapetla et al 2016)
Mice consisted of heterozygous D1 and D2–green fluorescent protein (GFP) mice on a C57/BL6 background as well as wild-type C57/BL6 mice and we always included biocytin in the intracellular solution, followed by immunocytochemistry for chicken ovalbumin upstream promoter transcription-factor interacting protein-2 (CTIP2) and PPE (Gerfen et al 1990; Arlotta et al 2008) to confirm, whenever possible, whether recordings were made from D1 or D2 SPNs (Fig. 1B)
In this paper we describe the developmental trajectory of identified D1 and D2 SPNs during the first postnatal weeks
Summary
The striatum is the main input nucleus of the basal ganglia and consists of two populations of projection neurons with distinct long-range outputs, the D1-expressing direct pathway spiny projection neurons (SPNs) and the D2-expressing indirect pathway SPNs (Day et al 2008; Gertler et al 2008), which differentially regulate motor behaviour and cognitive function (Graybiel et al 1994; Grillner et al 2005; Yin & Knowlton, 2006; Kravitz et al 2010; Tecuapetla et al 2016). Simultaneous quadruple patch-clamp recordings and the study of local connections between developing SPNs reveals that in the first postnatal week SPNs mainly form gap junctions with each other which only in later postnatal weeks are increasingly replaced by inhibitory synaptic connections These early inhibitory synaptic connections are precise and non-random and relative biases in synaptic connectivity
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