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Cognitive dysfunction in NF1 knock-out mice may result from altered vesicular trafficking of APP/DRD3 complex.

ABSTRACT: It has been estimated that more than 50% of patients with Neurofibromatosis type 1 (NF1) have neurobehavioral impairments which include attention deficit/hyperactivity disorder, visual/spatial learning disabilities, and a myriad of other cognitive developmental problems. The biological mechanisms by which NF1 gene mutations lead to such cognitive deficits are not well understood, although excessive Ras signaling and increased GABA mediated inhibition have been implicated. It is proposed that the cognitive deficits in NF1 are the result of dysfunctional cellular trafficking and localization of molecules downstream of the primary gene defect.To elucidate genes involved in the pathogenic process, gene expression analysis was performed comparing the expression profiles in various brain regions for control and Nf1+/- heterozygous mice. Gene expression analysis was performed for hippocampal samples dissected from postnatal day 10, 15, and 20 mice utilizing the Affymetrix Mouse Genome chip (Murine 430 2.0). Analysis of expression profiles between Nf1+/- and wild-type animals was focused on the hippocampus because of previous studies demonstrating alterations in hippocampal LTP in the Nf1+/- mice, and the region's importance in visual/spatial learning. Network analysis identified links between neurofibromin and kinesin genes, which were down regulated in the Nf1+/- mice at postnatal days 15 and 20.Through this analysis, it is proposed that neurofibromin forms a binding complex with amyloid precursor protein (APP) and through filamin proteins interacts with a dopamine receptor (Drd3). Though the effects of these interactions are not yet known, this information may provide novel ideas about the pathogenesis of cognitive defects in NF1 and may facilitate the development of novel targeted therapeutic interventions.

SUBMITTER: Donarum EA

PROVIDER: S-EPMC1434756 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Cognitive dysfunction in NF1 knock-out mice may result from altered vesicular trafficking of APP/DRD3 complex.

Donarum Elizabeth A EA Halperin Rebecca F RF Stephan Dietrich A DA Narayanan Vinodh V

BMC neuroscience 20060308

<h4>Background</h4>It has been estimated that more than 50% of patients with Neurofibromatosis type 1 (NF1) have neurobehavioral impairments which include attention deficit/hyperactivity disorder, visual/spatial learning disabilities, and a myriad of other cognitive developmental problems. The biological mechanisms by which NF1 gene mutations lead to such cognitive deficits are not well understood, although excessive Ras signaling and increased GABA mediated inhibition have been implicated. It i ...[more]

PMID: 16524466

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Project description:Retinal ischemia is a common pathomechanism in various eye diseases. Recently, evidence accumulated suggesting that the extracellular matrix (ECM) glycoprotein tenascin-C (Tnc) plays a key role in ischemic degeneration. However, the possible functional role of Tnc in retinal ischemia is not yet known. The aim of our study was to explore retinal function and rod-bipolar/photoreceptor cell degeneration in wild type (WT) and Tnc knock-out (KO) mice after ischemia/reperfusion (I/R) injury. Therefore, I/R was induced by increasing intraocular pressure in the right eye of wild type (WT I/R) and Tnc KO (KO I/R) mice. The left eye served as untreated control (WT CO and KO CO). Scotopic electroretinogram (ERG) recordings were performed to examine rod-bipolar and rod-photoreceptor cell function. Changes of Tnc, rod-bipolar cells, photoreceptors, retinal structure and apoptotic and synaptic alterations were analyzed by immunohistochemistry, Hematoxylin and Eosin staining, Western blot, and quantitative real time PCR. We found increased Tnc protein levels 3 days after ischemia, while Tnc immunoreactivity decreased after 7 days. Tnc mRNA expression was comparable in the ischemic retina. ERG measurements after 7 days showed lower a-/b-wave amplitudes in both ischemic groups. Nevertheless, the amplitudes in the KO I/R group were higher than in the WT I/R group. We observed retinal thinning in WT I/R mice after 3 and 7 days. Although compared to the KO CO group, retinal thinning was not observed in the KO I/R group until 7 days. The number of PKCα+ rod-bipolar cells, recoverin+ photoreceptor staining and Prkca and Rcvrn expression were comparable in all groups. However, reduced rhodopsin protein as well as Rho and Gnat1 mRNA expression levels of rod-photoreceptors were found in the WT I/R, but not in the KO I/R retina. Additionally, a lower number of activated caspase 3+ cells was observed in the KO I/R group. Finally, both ischemic groups displayed enhanced vesicular glutamate transporter 1 (vGlut1) levels. Collectively, KO mice showed diminished rod-photoreceptor degeneration and retinal dysfunction after I/R. Elevated vGlut1 levels after ischemia could be related to an impaired glutamatergic photoreceptor-bipolar cell signaling and excitotoxicity. Our study provides novel evidence that Tnc reinforces ischemic retinal degeneration, possibly by synaptic remodeling.

Dataset Information

Cognitive dysfunction in NF1 knock-out mice may result from altered vesicular trafficking of APP/DRD3 complex.

Publications

Cognitive dysfunction in NF1 knock-out mice may result from altered vesicular trafficking of APP/DRD3 complex.

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