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

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

Relationships among Parvalbumin-Immunoreactive Neuron Density, Phase-Locked Gamma Oscillations, and Autistic/Schizophrenic Symptoms in PDGFR-β Knock-Out and Control Mice

<div><p>Cognitive deficits and negative symptoms are important therapeutic targets for schizophrenia and autism disorders. Although reduction of phase-locked gamma oscillation has been suggested to be a result of reduced parvalbumin-immunoreactive (putatively, GABAergic) neurons, no direct correlations between these have been established in these disorders. In the present study, we investigated such relationships during pharmacological treatment with a newly synthesized drug, T-817MA, which displays neuroprotective and neurotrophic effects. In this study, we used platelet-derived growth factor receptor-β gene knockout (PDGFR-β KO) mice as an animal model of schizophrenia and autism. These mutant mice display a reduction in social behaviors; deficits in prepulse inhibition (PPI); reduced levels of parvalbumin-immunoreactive neurons in the medical prefrontal cortex, hippocampus, amygdala, and superior colliculus; and a deficit in of auditory phase-locked gamma oscillations. We found that oral administration of T-817MA ameliorated all these symptoms in the PDGFR-β KO mice. Furthermore, phase-locked gamma oscillations were significantly correlated with the density of parvalbumin-immunoreactive neurons, which was, in turn, correlated with PPI and behavioral parameters. These findings suggest that recovery of parvalbumin-immunoreactive neurons by pharmacological intervention relieved the reduction of phase-locked gamma oscillations and, consequently, ameliorated PPI and social behavioral deficits. Thus, our findings suggest that phase-locked gamma oscillations could be a useful physiological biomarker for abnormality of parvalbumin-immunoreactive neurons that may induce cognitive deficits and negative symptoms of schizophrenia and autism, as well as of effective pharmacological interventions in both humans and experimental animals.</p></div

T-817MA ameliorated PPI deficits in PDGFR-β KO mice.

<p>(A) Acoustic startle amplitudes measured in trials without a prepulse. No significant differences were observed in the acoustic startle amplitudes among the four groups of mice. Values indicate the mean ± SE. (B) PPI (% inhibition) at five different prepulse intensities (70, 72, 74, 78, and 82 dB). Statistical results by three-way ANOVAs indicated significant main effects of genotype and treatment. Cont-DW, control mice with distilled water (DW); Cont-T817, control mice with T-817MA; KO-DW, PDGFR-β KO mice with DW; KO-T817, PDGFR-β KO mice with T-817MA.</p

Comparison of peak-ITC (30.4–67.1 Hz) among the four groups.

<p>Peak-ITC was significantly lower in PDGFR-β KO mice administered with distilled water (KO-DW) compared to control mice administered with distilled water (Cont-DW) and PDGFR-β KO mice administered with T-817MA (KO-T817). aa, p<0.01 (Bonferroni test).</p

Photomicrographs of the medial prefrontal cortex (mPFC, A), CA3 subfield of the hippocampus (B), basolateral amygdala (BLA, C), and superior colliculus (SC, D) of the four groups of mice.

<p>Number of parvalbumin-immunoreactive neurons was decreased in PDGFR-<b>β</b> KO mice (KO-DW). Scale bar = 100 μm.</p

Significant correlations among neurophysiological, immunohistological, and behavioral parameters.

<p>(A) Significant correlation was observed between peak-ITC and parvalbumin-immunoreactive neuron density in the mPFC. (B-E) Significant relationships were observed between parvalbumin-immunoreactive neuron density in the mPFC and the duration of approaching (B), parvalbumin-immunoreactive neuron density in the mPFC and the duration of social sniffing (C), parvalbumin-immunoreactive neuron density in the mPFC and the duration of passive contact (D), parvalbumin-immunoreactive neuron density in the hippocampus (Hip) and the duration of approaching (E) (p<0.05). (F, G) Significant relationships were observed between parvalbumin-immunoreactive neuron density in the mPFC and % inhibition at 74 dB in the PPI test (F) and parvalbumin-immunoreactive neuron density in the hippocampus (Hip) and % inhibition at 74 dB in the PPI test (G) (p<0.05). Circles, Cont-DW; squares, Cont-T817; triangles, KO-DW; Crosses, KO-T817.</p