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

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.

Prefrontal cognitive deficits in mice with altered cerebral cortical GABAergic interneurons

“…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.…”

Rearing in enriched environment increases parvalbumin-positive small neurons in the amygdala and decreases anxiety-like behavior of male rats

“…Interneurons expressing PV exhibit the fast-spiking phenotype and have been suggested to be involved in gamma oscillations [5,6]. Disruption of gamma oscillation has been suggested to underlie psychiatric disorders such as schizophrenia [57] and autism [58] and may be attributable to deficits in GABAergic PV-positive interneurons [57,59,60]. Furthermore, adverse prenatal or early life events such as exposure to ethanol and maternal separation alter emotional responsiveness and the number of PV-positive interneurons in BLA, medial septum, medial prefrontal cortex, and hippocampus [61-64].…”

2,3,7,8-Tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam

“…8 Together, these findings suggest that TCDD affects the GABAergic neurons during brain development depending on gender. Because an altered GABAergic system and CaMKII activity have been observed in mouse models of ASD and individuals with schizophrenia suffer from social disturbances, [40][41][42][43] TCDD may increase autistic traits through the GABAergic system and CaMKII. Recently, perinatal TCDD exposure was reported to decrease the number of parvalbumin-immunoreactive neurons (putative inhibitory interneurons) in the limbic system, including the amygdala and hippocampus, in rats; 33 these findings suggest that alterations in the inhibitory interneurons in these brain regions partly mediate the effects of TCDD on higher brain functions.…”