Cognitive and Socio-Emotional Deficits in Platelet-Derived Growth Factor Receptor-β Gene Knockout Mice

Tokyo Medical and Dental University, Japan
PLoS ONE (Impact Factor: 3.23). 03/2011; 6(3):e18004. DOI: 10.1371/journal.pone.0018004
Source: PubMed

ABSTRACT Platelet-derived growth factor (PDGF) is a potent mitogen. Extensive in vivo studies of PDGF and its receptor (PDGFR) genes have reported that PDGF plays an important role in embryogenesis and development of the central nervous system (CNS). Furthermore, PDGF and the β subunit of the PDGF receptor (PDGFR-β) have been reported to be associated with schizophrenia and autism. However, no study has reported on the effects of PDGF deletion on mice behavior. Here we generated novel mutant mice (PDGFR-β KO) in which PDGFR-β was conditionally deleted in CNS neurons using the Cre/loxP system. Mice without the Cre transgene but with floxed PDGFR-β were used as controls. Both groups of mice reached adulthood without any apparent anatomical defects. These mice were further examined by conducting several behavioral tests for spatial memory, social interaction, conditioning, prepulse inhibition, and forced swimming. The test results indicated that the PDGFR-β KO mice show deficits in all of these areas. Furthermore, an immunohistochemical study of the PDGFR-β KO mice brain indicated that the number of parvalbumin (calcium-binding protein)-positive (i.e., putatively γ-aminobutyric acid-ergic) neurons was low in the amygdala, hippocampus, and medial prefrontal cortex. Neurophysiological studies indicated that sensory-evoked gamma oscillation was low in the PDGFR-β KO mice, consistent with the observed reduction in the number of parvalbumin-positive neurons. These results suggest that PDGFR-β plays an important role in cognitive and socioemotional functions, and that deficits in this receptor may partly underlie the cognitive and socioemotional deficits observed in schizophrenic and autistic patients.

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Available from: Susumu Urakawa, Dec 27, 2013
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    • "These findings suggest that PDGFR-β KO induces development and maturation deficits in Otx2- and PV-IR cells in the SC. These results further suggest that behavioral traits (socioemotional deficits) of PDGFR-β KO mice [48] might be ascribed partly to deficits in PV-positive GABAergic neurons in the SC of PDGFR-β KO mice. This idea is supported by previous studies; bilateral SC lesions reduced social behaviors [7, 8] and reduction of number of PV-containing GABAergic neuronsin the SC is associated with autism and schizophrenia with social deficits [17–19]. "
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    ABSTRACT: The superior colliculus (SC), a relay nucleus in the subcortical visual pathways, is implicated in socioemotional behaviors. Homeoprotein Otx2 and β subunit of receptors of platelet-derived growth factor (PDGFR- β ) have been suggested to play an important role in development of the visual system and development and maturation of GABAergic neurons. Although PDGFR- β -knockout (KO) mice displayed socio-emotional deficits associated with parvalbumin (PV-)immunoreactive (IR) neurons, their anatomical bases in the SC were unknown. In the present study, Otx2 and PV-immunolabeling in the adult mouse SC were investigated in the PDGFR- β KO mice. Although there were no differences in distribution patterns of Otx2 and PV-IR cells between the wild type and PDGFR- β KO mice, the mean numbers of both of the Otx2- and PV-IR cells were significantly reduced in the PDGFR- β KO mice. Furthermore, average diameters of Otx2- and PV-IR cells were significantly reduced in the PDGFR- β KO mice. These findings suggest that PDGFR- β plays a critical role in the functional development of the SC through its effects on Otx2- and PV-IR cells, provided specific roles of Otx2 protein and PV-IR cells in the development of SC neurons and visual information processing, respectively.
    11/2013; 2013(2):848265. DOI:10.1155/2013/848265
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    • "Contextual memory did not differ within the groups, even though the HGF and Plaur/HGF mice presented with nearly two-fold more PV + hippocampal interneurons . Previous studies have indicated that loss of PV + interneuron activity leads to impaired spatial memory [51] [52]. However, cued extinction was impaired in all the mutant genotypes, implying dysfunction of the MFC. "
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    ABSTRACT: Alterations of inhibitory GABAergic neurons are implicated in multiple psychiatric and neurological disorders, including schizophrenia, autism and epilepsy. In particular, interneuron deficits in prefrontal areas, along with presumed decreased inhibition, have been reported in several human patients. The majority of forebrain GABAergic interneurons arise from a single subcortical source before migrating to their final regional destination. Factors that govern the interneuron populations have been identified, demonstrating that a single gene mutation may globally affect forebrain structures or a single area. In particular, mice lacking the urokinase plasminogen activator receptor (Plaur) gene have decreased GABAergic interneurons in frontal and parietal, but not caudal, cortical regions. Plaur assists in the activation of hepatocyte growth factor/scatter factor (HGF/SF), and several of the interneuron deficits are correlated with decreased levels of HGF/SF. In some cortical regions, the interneuron deficit can be remediated by endogenous overexpression of HGF/SF. In this study, we demonstrate decreased parvalbumin-expressing interneurons in the medial frontal cortex, but not in the hippocampus or basal lateral amygdala in the Plaur null mouse. The Plaur null mouse demonstrates impaired medial frontal cortical function in extinction of cued fear conditioning and the inability to form attentional sets. Endogenous HGF/SF overexpression increased the number of PV-expressing cells in medial frontal cortical areas to levels greater than found in wildtype mice, but did not remediate the behavioral deficits. These data suggest that proper medial frontal cortical function is dependent upon optimum levels of inhibition and that a deficit or excess of interneuron numbers impairs normal cognition.
    Behavioural brain research 11/2013; 259. DOI:10.1016/j.bbr.2013.10.051 · 3.03 Impact Factor
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    • "drome ( Kalanithi et al . 2005 ) . As de - duced from these , nestin – Cre mediated PDGFRB gene knockout in neural cells in embryonic periods reduces the number of parvalbumin ( calcium - binding protein ) - pos - itive ( i . e . , putatively GABAergic ) neurons in the amygda - la , hippocampus , and medial prefrontal cortex of adult mouse brain ( Nguyen et al . 2011 ) . These mice show behavioral and electrophysiological abnormalities character - istic to autism or schizophrenia , including defective social behavior , spatial memory and sensory - evoked gamma os - cillations . Genetic linkage analyses have shown PDGFRB to be located on chromosome 5q31 – q32 ( Kalanithi et al . 2005 ) , which contai"
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    ABSTRACT: The four platelet-derived growth factor (PDGF) ligands and PDGF receptors (PDGFRs), α and β (PDGFRA, PDGFRB), are essential proteins that are expressed during embryonic and mature nervous systems, i.e., in neural progenitors, neurons, astrocytes, oligodendrocytes, and vascular cells. PDGF exerts essential roles from the gastrulation period to adult neuronal maintenance by contributing to the regulation of development of preplacodal progenitors, placodal ectoderm, and neural crest cells to adult neural progenitors, in coordinating with other factors. In adulthood, PDGF plays critical roles for maintenance of many specific cell types in the nervous system together with vascular cells through controlling the blood brain barrier homeostasis. At injury or various stresses, PDGF modulates neuronal excitability through adjusting various ion channels, and affecting synaptic plasticity and function. Furthermore, PDGF stimulates survival signals, majorly PI3-K/Akt pathway but also other ways, rescuing cells from apoptosis. Studies imply an involvement of PDGF in dendrite spine morphology, being critical for memory in the developing brain. Recent studies suggest association of PDGF genes with neuropsychiatric disorders. In this review, we will describe the roles of PDGF in the nervous system, from the discovery to recent findings, in order to understand the broad spectrum of PDGF in the nervous system. Recent development of pharmacological and replacement therapies targeting the PDGF system is discussed.
    Journal of Neuroimmune Pharmacology 06/2013; 9(2). DOI:10.1007/s11481-013-9479-z · 4.11 Impact Factor
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