Dataset Information

Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1^+/- mice.

ABSTRACT: Schizophrenia is a common and severe mental disorder arising from complex gene-environment interactions affecting brain development and functioning. While a consensus on the neuroanatomical correlates of schizophrenia is emerging, much of its fundamental pathobiology remains unknown. In this study, we explore brain morphometry in mice with genetic susceptibility and phenotypic relevance to schizophrenia (Brd1^+/- mice) using postmortem 3D MR imaging coupled with histology, immunostaining and regional mRNA marker analysis. In agreement with recent large-scale schizophrenia neuroimaging studies, Brd1^+/- mice displayed subcortical abnormalities, including volumetric reductions of amygdala and striatum. Interestingly, we demonstrate that structural alteration in striatum correlates with a general loss of striatal neurons, differentially impacting subpopulations of medium-sized spiny neurons and thus potentially striatal output. Akin to parvalbumin interneuron dysfunction in patients, a decline in parvalbumin expression was noted in the developing cortex of Brd1^+/- mice, mainly driven by neuronal loss within or near cortical layer V, which is rich in corticostriatal projection neurons. Collectively, our study highlights the translational value of the Brd1^+/- mouse as a pre-clinical tool for schizophrenia research and provides novel insight into its developmental, structural, and cellular pathology.

SUBMITTER: Qvist P

PROVIDER: S-EPMC6220279 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1<sup>+/-</sup> mice.

Qvist Per P Eskildsen Simon F SF Hansen Brian B Baragji Mohammad M Ringgaard Steffen S Roovers Jolien J Paternoster Veerle V Molgaard Simon S Corydon Thomas Juhl TJ Stødkilde-Jørgensen Hans H Glerup Simon S Mors Ole O Wegener Gregers G Nyengaard Jens R JR Børglum Anders D AD Christensen Jane H JH

Scientific reports 20181107 1

Schizophrenia is a common and severe mental disorder arising from complex gene-environment interactions affecting brain development and functioning. While a consensus on the neuroanatomical correlates of schizophrenia is emerging, much of its fundamental pathobiology remains unknown. In this study, we explore brain morphometry in mice with genetic susceptibility and phenotypic relevance to schizophrenia (Brd1<sup>+/-</sup> mice) using postmortem 3D MR imaging coupled with histology, immunostaini ...[more]

PMID: 30405140

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Project description:Precise identification of neuronal populations is a major challenge in neuroscience. In the striatum, more than 95% of neurons are GABAergic medium-sized spiny neurons (MSNs), which form two intermingled populations distinguished by their projections and protein content. Those expressing dopamine D(1)-receptors (D1Rs) project preferentially to the substantia nigra pars reticulata (SNr), whereas those expressing dopamine D(2)- receptors (D2Rs) project preferentially to the lateral part of the globus pallidus (LGP). The degree of segregation of these populations has been a continuous subject of debate, and the recent introduction of bacterial artificial chromosome (BAC) transgenic mice expressing fluorescent proteins driven by specific promoters was a major progress to facilitate striatal neuron identification. However, the fraction of MSNs labeled in these mice has been recently called into question, casting doubt on the generality of results obtained with such approaches. Here, we performed an in-depth quantitative analysis of striatal neurons in drd1a-EGFP and drd2-EGFP mice. We first quantified neuronal and non-neuronal populations in the striatum, based on nuclear staining with TO-PRO-3, and immunolabeling for NeuN, DARPP-32 (dopamine- and cAMP-regulated phosphoprotein Mr approximately 32,000), and various markers for interneurons. TO-PRO-3 staining was sufficient to identify MSNs by their typical nuclear morphology and, with a good probability, interneuron populations. In drd1a-EGFP/drd2-EGFP double transgenic mice all MSNs expressed EGFP, which was driven in about half of them by drd1a promoter. Retrograde labeling showed that all MSNs projecting to the SNr expressed D1R and very few D2R (<1%). In contrast, our results were compatible with the existence of some D1R-EGFP-expressing fibers giving off terminals in the LGP. Thus, our study shows that nuclear staining is a simple method for identifying MSNs and other striatal neurons. It also unambiguously confirms the degree of segregation of MSNs in the mouse striatum and allows the full exploitation of results obtained with BAC-transgenic mice.

Project description:Slowly varying activity in the striatum, the main Basal Ganglia input structure, is important for the learning and execution of movement sequences. Striatal medium spiny neurons (MSNs) form cell assemblies whose population firing rates vary coherently on slow behaviourally relevant timescales. It has been shown that such activity emerges in a model of a local MSN network but only at realistic connectivities of 10 ~ 20% and only when MSN generated inhibitory post-synaptic potentials (IPSPs) are realistically sized. Here we suggest a reason for this. We investigate how MSN network generated population activity interacts with temporally varying cortical driving activity, as would occur in a behavioural task. We find that at unrealistically high connectivity a stable winners-take-all type regime is found where network activity separates into fixed stimulus dependent regularly firing and quiescent components. In this regime only a small number of population firing rate components interact with cortical stimulus variations. Around 15% connectivity a transition to a more dynamically active regime occurs where all cells constantly switch between activity and quiescence. In this low connectivity regime, MSN population components wander randomly and here too are independent of variations in cortical driving. Only in the transition regime do weak changes in cortical driving interact with many population components so that sequential cell assemblies are reproducibly activated for many hundreds of milliseconds after stimulus onset and peri-stimulus time histograms display strong stimulus and temporal specificity. We show that, remarkably, this activity is maximized at striatally realistic connectivities and IPSP sizes. Thus, we suggest the local MSN network has optimal characteristics - it is neither too stable to respond in a dynamically complex temporally extended way to cortical variations, nor is it too unstable to respond in a consistent repeatable way. Rather, it is optimized to generate stimulus dependent activity patterns for long periods after variations in cortical excitation.

Dataset Information

Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1^+/- mice.

Publications

Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1<sup>+/-</sup> mice.

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Dataset Information

Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1+/- mice.

Publications

Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1<sup>+/-</sup> mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Brain volumetric alterations accompanied with loss of striatal medium-sized spiny neurons and cortical parvalbumin expressing interneurons in Brd1^+/- mice.