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.

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A dysfunctional striatum is thought to contribute to neurodevelopmental disorders such as ADHD, Tourette's syndrome and OCD. Insight into these disorders is reliant on an understanding of the normal development of the striatal cellular and circuit properties. Here we combined whole-cell patch-clamp electrophysiology and anatomical reconstructions of D1 and D2 striatal projection neurons (SPNs) in brain slices to characterize the development of the electrophysiological and morphological properties as well as their long-range and local inputs during the first three postnatal weeks. Overall, we find that many properties develop in parallel but we make several key observations. Firstly, that the electrophysiological properties of young D1 SPNs are more mature and that distinctions between D1 and D2 SPNs become apparent in the second postnatal week. Secondly, that dendrites and spines as well as excitatory inputs from cortex develop in parallel with cortical inputs exhibiting a prolonged period of maturation involving changes in postsynaptic glutamate receptors. Lastly, that initial local connections between striatal SPNs consist of gap junctions, which are gradually replaced by inhibitory synaptic connections. Interestingly, relative biases in inhibitory synaptic connectivity seen between SPNs in adulthood, such as a high connectivity between D2 SPNs, are already evident in the second postnatal week. Combined, these results provide an experimental framework for future investigations of striatal neurodevelopmental disorders and show that many of the cellular and circuit properties are established in the first and second postnatal weeks suggesting intrinsic programs guide their development. Significance StatementNormal brain development involves the formation of neurons, which develop correct electrical and morphological properties and are precisely connected with each other in a neural circuit. In neurodevelopmental disorders these processes go awry leading to behavioral and cognitive problems later in life. Here we provide for the first time a detailed quantitative description of the cellular and circuit properties of the two main neuron types of the striatum during the first postnatal weeks. This can form an experimental framework for future studies into neurodevelopmental disorders. We find that most of the properties for both types of striatal neuron develop in parallel and are already established by the second postnatal week suggesting a key role for intrinsic programs in guiding their development.

Heterogeneous populations of neural progenitors in the embryonic lateral ganglionic eminence (LGE) generate all GABAergic spiny projection neurons (SPNs) found in the striatum. Here we investigate how this diversity in neural progenitors relates to diversity of adult striatal neurons and circuits. Using a combination of in utero electroporation to fluorescently pulse-label striatal neural progenitors in the LGE, brain slice electrophysiology, electrical and optogenetic circuit mapping and immunohistochemistry, we characterise a population of neural progenitors enriched for apical intermediate progenitors (aIPs) and a distinct population of other progenitors (OPs) and their neural offspring. We find that neural progenitor origin has subtle but significant effects on the properties of striatal SPNs. Although aIP and OP progenitors can both generate D1-expressing direct pathway as well as D2-expressing indirect pathway SPNs found intermingled in the striatum, the aIP derived SPNs are found in more medial aspects of the striatum, exhibit more complex dendritic arbors with higher spine density and differentially sample cortical input. Moreover, optogenetic circuit mapping of the aIP derived neurons show that they further integrate within striatal circuits and innervate both local D1 and D2 SPNs. These results show that it is possible to fluorescently pulse-label distinct neural progenitor pools within the LGE and provide the first evidence that neural progenitor heterogeneity can contribute to the diversity of striatal SPNs.

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