Genetic, environmental and neurodevelopmental factors are thought to
underlie the onset of neuropsychiatric disorders such as schizophrenia.
How these risk factors collectively contribute to pathology is unclear.
Here, we present a mouse model of prenatal intracerebral hemorrhage—an
identified risk factor for schizophrenia—using a serum-exposure
paradigm. This model exhibits behavioral, neurochemical and
schizophrenia-related gene expression alterations in adult females.
Behavioral alterations in amphetamine-induced locomotion, prepulse
inhibition, thigmotaxis and social interaction—in addition to increases
in tyrosine hydroxylase-positive dopaminergic cells in the substantia
nigra and ventral tegmental area and decreases in parvalbumin-positive
cells in the prefrontal cortex—were induced upon prenatal serum
exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was
identified as a key molecular initiator of schizophrenia-like sequelae
induced by serum. Prenatal exposure to LPA alone phenocopied many of the
schizophrenia-like alterations seen in the serum model, whereas
pretreatment with an antagonist against the LPA receptor subtype LPA1
prevented many of the behavioral and neurochemical alterations. In
addition, both prenatal serum and LPA exposure altered the expression of
many genes and pathways related to schizophrenia, including the
expression of Grin2b, Slc17a7 and Grid1. These findings demonstrate that
aberrant LPA receptor signaling associated with fetal brain hemorrhage
may contribute to the development of some neuropsychiatric disorders.
underlie the onset of neuropsychiatric disorders such as schizophrenia.
How these risk factors collectively contribute to pathology is unclear.
Here, we present a mouse model of prenatal intracerebral hemorrhage—an
identified risk factor for schizophrenia—using a serum-exposure
paradigm. This model exhibits behavioral, neurochemical and
schizophrenia-related gene expression alterations in adult females.
Behavioral alterations in amphetamine-induced locomotion, prepulse
inhibition, thigmotaxis and social interaction—in addition to increases
in tyrosine hydroxylase-positive dopaminergic cells in the substantia
nigra and ventral tegmental area and decreases in parvalbumin-positive
cells in the prefrontal cortex—were induced upon prenatal serum
exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was
identified as a key molecular initiator of schizophrenia-like sequelae
induced by serum. Prenatal exposure to LPA alone phenocopied many of the
schizophrenia-like alterations seen in the serum model, whereas
pretreatment with an antagonist against the LPA receptor subtype LPA1
prevented many of the behavioral and neurochemical alterations. In
addition, both prenatal serum and LPA exposure altered the expression of
many genes and pathways related to schizophrenia, including the
expression of Grin2b, Slc17a7 and Grid1. These findings demonstrate that
aberrant LPA receptor signaling associated with fetal brain hemorrhage
may contribute to the development of some neuropsychiatric disorders.
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