Altered parvalbumin-positive neuron distribution in basal ganglia of individual with Tourette syndrome

Child Study Center and Department of Neurobiology, Yale University, New Haven, CT 06520.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2005; 102(37):13307-12. DOI: 10.1073/pnas.0502624102
Source: PubMed


Tourette syndrome (TS) is a childhood neuropsychiatric disorder characterized by motor and vocal tics. Imaging studies found alterations in caudate (Cd) and putamen volumes. To investigate possible alterations in cell populations, postmortem basal ganglia tissue from individuals with TS and normal controls was analyzed by using unbiased stereological techniques. A markedly higher total neuron number was found in the globus pallidus pars interna (GPi) of TS. In contrast, a lower neuron number and density was observed in the globus pallidus pars externa and in the Cd. An increased number and proportion of the GPi neurons were positive for the calcium-binding protein parvalbumin in tissue from TS subjects, whereas lower densities of parvalbumin-positive interneurons were observed in both the Cd and putamen of TS subjects. This change is consistent with a developmental defect in tangential migration of some GABAergic neurons. The imbalance in striatal and GPi inhibitory neuron distribution suggests that the functional dynamics of cortico-striato-thalamic circuitry are fundamentally altered in severe, persistent TS.

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Available from: Michael L Schwartz, Oct 10, 2015
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    • "Recent work has suggested that a deficit in cortical GABAergic inhibitory transmission may contribute to symptoms found in TS: GABA-related genes have been associated with risk for TS and with symptom severity (Fernandez et al. 2012; Tian et al. 2011); serum GABA levels are reduced in TS patients; and medication affecting the GABAergic system has been shown to reduce tics (Wang et al. 2012). Furthermore, altered GABA-A receptors and reduced density of GABAergic interneurons (Kalanithi et al. 2005; Lerner et al. 2012) have been shown in TS. GABA concentration can be measured in vivo with edited magnetic resonance spectroscopy (MRS) (Mescher et al. 1998; Puts and Edden 2012). "
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    ABSTRACT: Tourette Syndrome (TS) is characterized by the presence of chronic tics. Individuals with TS often report difficulty with ignoring (habituating to) tactile sensations and some patients perceive that this contributes to a "premonitory urge" to tic. While common, the physiological basis of impaired tactile processing in TS, and indeed tics themselves, remain poorly understood. It has been well established that GABAergic processing plays an important role in shaping the neurophysiological response to tactile stimulation. Further, there are multiple lines of evidence suggesting that a deficit in GABAergic transmission may contribute to symptoms found in TS. In this study, GABA-edited MRS was combined with a battery of vibrotactile tasks to investigate the role of GABA and atypical sensory processing in children with TS. Our results show reduced primary sensorimotor (SM1) GABA concentration in children with TS compared to healthy controls (HC), as well as patterns of impaired performance on tactile detection and adaptation tasks, consistent with altered GABAergic function. Moreover, in children with TS, SM1 GABA concentration correlated with motor tic severity, linking the core feature of TS directly to in vivo brain neurochemistry. There was an absence of the typical correlation between GABA and frequency discrimination performance in TS as was seen in HC. These data show that reduced GABA concentration in TS may contribute to both motor tics and sensory impairments in children with TS. Understanding the mechanisms of altered sensory processing in TS may provide a foundation for novel interventions to alleviate these symptoms. Copyright © 2015, Journal of Neurophysiology.
    Journal of Neurophysiology 06/2015; 114(2):jn.00060.2015. DOI:10.1152/jn.00060.2015 · 2.89 Impact Factor
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    • "Reversibly silencing inhibitory interneurons can be quite useful with our growing knowledge of the behavioral contingencies that determine interclass activity differences (Letzkus et al., 2011; Lapray et al., 2012; Pi et al., 2013), as well as their differential role in network oscillations (Roux et al., 2014). This genetically targeted manipulation can also be used in the study of diseases with an evolving dysfunction of specific interneuronal cell types (Gernert et al., 2000, 2002; Kalanithi et al., 2005; Kataoka et al., 2010; Gittis et al., 2011; Kim et al., 2014), particularly to examine trial-bytrial , or time-locked variability in electrophysiology and behavior in the disease state. "
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    ABSTRACT: The evolution of genetically targeted tools has begun to allow us to dissect anatomically and functionally heterogeneous interneurons, and to probe circuit function from synapses to behavior. Over the last decade, these tools have been used widely to visualize neurons in a cell type-specific manner, and engage them to activate and inactivate with exquisite precision. In this process, we have expanded our understanding of interneuron diversity, their functional connectivity, and how selective inhibitory circuits contribute to behavior. Here we discuss the relative assets of genetically encoded fluorescent proteins (FPs), viral tracing methods, optogenetics, chemical genetics, and biosensors in the study of inhibitory interneurons and their respective circuits.
    Frontiers in Neural Circuits 10/2014; 8:124. DOI:10.3389/fncir.2014.00124 · 3.60 Impact Factor
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    • "A similar decrease in the maturation of PV interneurons in the cortex is caused by chronic perinatal hypoxia, which models prematurity [49]. The loss or dysfunction of GABAergic interneurons has been implicated in various psychiatric disorders [12], [50]–[56]. Early studies of mRNA expression in post mortem tissue identified a decrease in Gad1 mRNA (coding for the Gad67 protein) in the prefrontal cortex of individuals with schizophrenia or bipolar disorder [57], [58]. Follow up studies have confirmed changes in the expression in Gad1 mRNA, and other GABAergic molecules such as PV, Sst, and NPY, in individuals with psychosis [44], [57], [59]–[61]. "
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    ABSTRACT: Fibroblast growth factors (Fgfs) and their receptors (Fgfr) are expressed in the developing and adult CNS. Previous studies demonstrated a decrease in cortical interneurons and locomotor hyperactivity in mice with a conditional Fgfr1 deletion generated in radial glial cells during midneurogenesis (Fgfr1 f/f ;hGfapCre+). Here, we report earlier and more extensive inactivation of Fgfr1 in neuroepithelial cells of the CNS (Fgfr1 f/f ;NesCre+). Similar to findings in Fgfr1 f/f ;hGfapCre+ mice, parvalbumin positive (PV+) cortical interneurons are also decreased in the neocortex of Fgfr1f/f;NesCre+ mice when compared to control littermates (Fgfr1f/f). Fgfr1f/f;NesCre+ embryos do not differ from controls in the initial specification of GABAergic cells in the ganglionic eminence (GE) as assessed by in situ hybridization for Dlx2, Mash1 and Nkx2. Equal numbers of GABAergic neuron precursors genetically labeled with green fluorescent protein (GFP) were observed at P0 in Fgfr1 f/f ;hGfapCre+;Gad1-GFP mutant mice. However, fewer GFP+ and GFP+/PV+ interneurons were observed in these mutants at adulthood, indicating that a decrease in cortical interneuron markers is occurring postnatally. Fgfr1 is expressed in cortical astrocytes in the postnatal brain. To test whether the astrocytes of mice lacking Fgfr1 are less capable of supporting interneurons, we co-cultured wild type Gad1-GFP+ interneuron precursors isolated from the medial GE (MGE) with astrocytes from Fgfr1f/f control or Fgfr1 f/f ;hGfapCre+ mice. Interneurons grown on Fgfr1 deficient astrocytes had small soma size and fewer neurites per cell, but no differences in cell survival. Decreased soma size of Gad67 immunopositive interneurons was also observed in the cortex of adult Fgfr1 f/f ;NesCre+ mice. Our data indicate that astrocytes from Fgfr1 mutants are impaired in supporting the maturation of cortical GABAergic neurons in the postnatal period. This model may elucidate potential mechanisms of impaired PV interneuron maturation relevant to neuropsychiatric disorders that develop in childhood and adolescence. Citation: Smith KM, Maragnoli ME, Phull PM, Tran KM, Choubey L, et al. (2014) Fgfr1 Inactivation in the Mouse Telencephalon Results in Impaired Maturation of Interneurons Expressing Parvalbumin. PLoS ONE 9(8): e103696. doi:10.1371/journal.pone.0103696
    PLoS ONE 08/2014; 9(8). DOI:10.1371/journal.pone.0103696 · 3.23 Impact Factor
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