Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome

Centonze, Diego; Rossi, Silvia; Mercaldo, Valentina; Napoli, Ilaria; Ciotti, Maria Teresa; Chiara, Valentina De; Musella, Alessandra; Prosperetti, Chiara; Calabresi, Paolo; Bernardi, Giorgio; Bagni, Claudia

doi:10.1016/j.biopsych.2007.09.008

Cited by 150 publications

(150 citation statements)

References 66 publications

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…Both Rett syndrome (Mecp2 mutant mice) (41) and Down's syndrome (Ts65Dn mice) (42) animal models show increased inhibitory drive. The Fragile X animal model (Fmr1 knockout mice) shows reduced excitatory drive onto cortical GABAergic interneurons (43) as well as increased GABAergic inhibition in striatum (44). Taken together, these studies of other neurodevelopmental disorders are consistent with our findings in NF1.…”

Section: Discussionsupporting

confidence: 89%

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Shilyansky

Karlsgodt

Cummings

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

145

150

View full text Add to dashboard Cite

Neurofibromatosis type I (NF1) is one of the most common singlegene causes of learning disabilities. Here, we use behavioral working memory probes and electrophysiological studies in a mouse model of NF1 (Nf1 heterozygous null mutants; Nf1 +/− ) to demonstrate that (i) Neurofibromin regulates prefrontal and striatal inhibitory networks, specifically activity-dependent GABA release and (ii) is required for working memory performance, with inhibitiondependent working memory deficits seen in Nf1 +/− mice. We find that increased inhibition in medial prefrontal cortex (mPFC) is sufficient to alter persistent activity in a biophysical model of an mPFC microcircuit, suggesting a possible mechanism for Nf1 +/− working memory deficits. Accordingly, working memory assays applied during functional MRI (fMRI) studies in human subjects with NF1 reveal hypoactivation of corticostriatal networks, which is associated with impaired working memory performance. Collectively, these integrative mouse and human studies reveal molecular and cellular mechanisms contributing to working memory deficits in NF1.GABA | Ras | prefrontal cortex | learning disability | neurofibromatosis type I N eurofibromatosis type 1 (NF1) is a valuable model for understanding mechanisms of learning disabilities (1). NF1 is a common genetic disorder (incidence 1:3,000) that results from mutations in a single gene (Nf1) that encodes the neurofibromin protein (2, 3). Specific deficits in the domains of visuospatial and executive functions are among the most common cognitive deficits associated with this syndrome (1,4,5). Previous mechanistic studies in a mouse model of NF1 (Nf1 heterozygous null mutants or Nf1 +/− ) demonstrated that neurofibromin modulates Rasdependent GABA release in the hippocampus, which in turn modulates long-term potentiation (LTP) and hippocampaldependent learning (6, 7). However, the mechanisms underlying frontal executive dysfunction in NF1, including prominent working memory deficits (5), are unknown. Therefore, to investigate mechanisms underlying working memory deficits associated with the NF1 mutation we carried out parallel experiments in mice and humans.Working memory is a cognitive construct involving the ability to hold and update information transiently in mind in the service of higher-order cognitive activities. Executive functions, including working memory, are thought to depend on common corticostriatal networks (8-11). Therefore, our experiments focused on frontal corticostriatal circuitry, with an emphasis on the dorsolateral prefrontal cortex (DLPFC) in humans, thought to be critical for working memory (12), and its functionally analogous structure in rodents, the medial prefrontal cortex (mPFC) (13,14).Here, we report Ras-dependent increases in GABA release in the mPFC and striatum of the Nf1 +/− mouse model. Increased GABAergic inhibition is likely to be responsible for the working memory deficits that we found in the Nf1 +/− mice because these deficits could be reversed with a drug that decreased inhibition. Further,...

show abstract

Section: Discussionsupporting

confidence: 89%

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Shilyansky

Karlsgodt

Cummings

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

145

150

View full text Add to dashboard Cite

show abstract

“…Another electrophysiological study noted that although GABAergic synapses appeared to be reduced in the striatum of knockout mice, there was a significant increase in the frequency of spontaneous and miniature inhibitory postsynaptic currents, which was suggestive of abnormal GABA transmission (Centonze et al, 2008). Furthermore, HPLC analysis of amino acids in PND 28-31 female knockout mice brains in another study revealed a significant increase in GABA levels in the striatum (Gruss and Braun, 2004).…”

Section: The Gabaergic System and Fragile X Syndromementioning

confidence: 96%

“…Similarly, GAD65 over-expression in adult Fmr1 knockout mice may be the result of cellular compensation for decreased GABA receptor-mediated inhibition. The results from a study demonstrating an increase in the frequency of GABAergic spontaneous and miniature inhibitory postsynaptic currents in acute brain slices from the striatum of adult Fmr1 knockout mice were interpreted as being indicative of increased GABA release at nerve terminals (Centonze et al, 2008). These effects might be a consequence of altered GABAergic enzyme expression and the accompanying down-regulation of the α1 and β2 subunits.…”

Section: Gabaergic Protein Expression and Neuronal Development In Thementioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

View full text Add to dashboard Cite

The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

show abstract

“…(c,d) Systems-level convergence in ASD. (c) White matter tract and functional connectivity abnormalities [126,147-150,152,153] (images reproduced with permission from Mark Bastin, University of Edinburgh, UK); (d) excitation/inhibition network imbalances [93,132,136-141], (e-g) Genetic convergence at the cellular and molecular levels. ASD-associated genes implicated in (e) activity-dependent protein synthesis [17,21,23,79,109,113-123], (f) neuronal activity [21,22,25,70,105-112], and (g) neuronal cell adhesion [20-22,34-37,49-52,68,75,79,93,109,126-129,131-137].…”

Section: Emerging Biological Themesmentioning

confidence: 99%

“…In addition, Shank3 knockout decreases cortical excitatory transmission [138]. Fmr1 knockout mice show several excitatory/inhibitory imbalances, including impaired inhibitory transmission in the amygdala [139], decreased excitatory inputs into inhibitory neurons in the cortex [140], and an increased inhibitory transmission in the striatum [141]. …”

Section: Emerging Biological Themesmentioning

confidence: 99%

Autism genetics: searching for specificity and convergence

2012

View full text Add to dashboard Cite

show abstract

Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome

Cited by 150 publications

References 66 publications

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

Autism genetics: searching for specificity and convergence

Contact Info

Product

Resources

About