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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.

SUBMITTER: Krajeski RN

PROVIDER: S-EPMC6900874 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Krajeski Rohan N RN Macey-Dare Anežka A van Heusden Fran F Ebrahimjee Farid F Ellender Tommas J TJ

The Journal of physiology 20191010 21

<h4>Key points</h4>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 properti ...[more]

PMID: 31531863

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Project description:Many neurological disorders and diseases including drug addiction are associated with specific neuronal cell types in the brain. The striatum, a region that plays a critically important role in the development of addictive drug-related behavior, provides a good example of the cellular heterogeneity challenges associated with analyses of specific neuronal cell types. Such studies are needed to identify the adaptive changes in neuroproteomic signaling that occur in response to diseases such as addiction. The striatum contains two major cell types, D1 and D2 type dopaminoceptive medium spiny neurons (MSNs), whose cell bodies and processes are intermingled throughout this region. Since little is known about the proteomes of these two neuronal cell populations, we have begun to address this challenge by using fluorescence-activated nuclear sorting (FANS) to isolate nuclei-containing fractions from striatum from D1 and D2 "Translating Ribosome Affinity Purification" (TRAP) mice. This approach enabled us to devise and implement a robust and reproducible workflow for preparing samples from specific MSN cell types for mass spectrometry analyses. These analyses quantified at least 685 proteins in each of four biological replicates of 50 K sorted nuclei from two D1 mice/replicate and from each of four biological replicates of 50 K sorted nuclei from two D2 mice/replicate. Proteome analyses identified 87 proteins that were differentially expressed in D1 versus D2 MSN nuclei and principal component analysis (PCA) of these proteins separated the 8 biological replicates into specific cell types. Central network analysis of the 87 differentially expressed proteins identified Hnrnpd and Hnmpa2b1 in D1 and Cct2 and Cct7 in D2 as potential central interactors. This workflow can now be used to improve our understanding of many neurological diseases including characterizing the short and long-term impact of drugs of abuse on the proteomes of these two dopaminoceptive neuronal populations.

Project description:L-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease. To profile the cell-type-specific responses of striatal spiny projection neurons (SPNs) to striatal dopamine depletion, we conducted TRAP analysis of the two major classes of these neurons: dSPNs that express the dopamine receptor 1a (Drd1a), and iSPNs that express the dopamine receptor 2 (Drd2). To disrupt dopamine innervation to both of these SPN populations that reside in the striatum, we injected the neurotoxin 6-hydroxydopamine (6-OHDA), unilaterally, in the medial forebrain bundle (MFB) in hemizygous Drd1-TRAP and Drd2-TRAP adult (9-14 weeks) male mice (kept on a C57BL/6J genetic background). This lesion procedure causes nigral dopamine cell death within a few days, along with a widespread and near-complete loss of dopaminergic innervation to the entire dorsal striatum on one side of the brain (a hemiparkinsonian model). We first examined the effects of dopamine depletion alone, compared to a mock lesion (ascorbate / saline injected). We then examined the effects of chronic levodopa treatment upon the molecular profiles of dopamine- depleted dSPNs and iSPNs, with two dose regimens. The ‘high-dose’ L-DOPA regimen (3 mg/kg on days 1-3, followed by 6 mg/kg on days 4-9) was expected to induce severe dyskinesia in all MFB-lesioned mice. The low-dose L-DOPA regimen (1 mg/kg on days 1-3, followed by 2 mg/kg on days 4-9) was expected to reverse limb use asymmetry without causing conspicuous dyskinesias. To equalize the effects of stress and handling across all groups, including control groups, all mice were equally handled and thus received saline injections when not receiving levodopa injections. Each treatment group contained 7-10 replicates. TRAP-purified mRNAs from either Drd1a- or Drd2-expressing SPNs were reverse-transcribed, amplified, and used to interrogate Affymetrix 430_2.0 GeneChip microarrays.

Dataset Information

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

Publications

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

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