Neurochemical Changes in LPA1 Receptor Deficient Mice – A Putative Model of Schizophrenia

Abstract

LPA1 is a Gi-coupled seven transmembrane receptor with high affinity for the ligand lysophosphatidic acid. We have investigated the effect of targeted deletion at the lpa1 locus on evoked release of amino acids from hippocampal slices, using in vitro superfusion techniques, and evoked 5-HT efflux from the dorsal raphe nucleus, using in vitro fast cyclic voltammetry. Superfusion of hippocampal slices revealed that basal levels of tyrosine, aspartate and glutamate release were significantly increased while K+ -evoked release of glutamate and GABA were significantly decreased in lpa1(-/-) mice. Fast cyclic voltammetry measurements in the dorsal raphe nucleus demonstrated significant decreases in electrically evoked 5-HT efflux in lpa1(-/-) mice. In summary, these data demonstrate that the lpa1 mutation produces a number of changes in neurotransmitters that have been associated with a schizophrenic-like pathology.

Sharpening the edges of understanding the structure/function of the LPA1 receptor: Expression in cancer and mechanisms of regulation☆

“…Interestingly, the changes in basal amino acid and monoamine levels in the brains of nullmutant mice were similar to neurochemical changes that occur in schizophrenia, suggesting that mice lacking the LPA1 receptor provide a model for this disease [15]. Their reduced ability to evoke gamma-aminobutyric acid (GABA) and glutamate release from the hippocampus, dysmorphic craniofacial features and decrease in 5-HT utilization is consistent with features implicated in the pathology of schizophrenia [11,15]. Thus, a major role of the LPA1 receptor occurs during central nervous system development and maintenance of a normal operation system.…”

“…Additional studies of null-mutant LPA1 receptor mice suggested that incisor overgrowth might contribute to postnatal death, especially when untreated [11]. Interestingly, the changes in basal amino acid and monoamine levels in the brains of nullmutant mice were similar to neurochemical changes that occur in schizophrenia, suggesting that mice lacking the LPA1 receptor provide a model for this disease [15]. Their reduced ability to evoke gamma-aminobutyric acid (GABA) and glutamate release from the hippocampus, dysmorphic craniofacial features and decrease in 5-HT utilization is consistent with features implicated in the pathology of schizophrenia [11,15].…”

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…Indeed, the removal of LPA 1 signaling during development signifi cantly alters the neuropsychiatric profi le of mice. Lpar1 Ϫ/Ϫ mice exhibit defi cits in prepulse inhibition of the startle refl ex, altered levels of serotonin, abnormalities in glutamatergic synapses (94,210,211), and a reduction in entorhinal cortex ␥ oscillations and parvalbumin-positive neurons (212). Furthermore, maLPA 1 Ϫ/Ϫ mice display defects in olfaction, pain sensing, exploration, anxiety, and memory retention in addition to cortical developmental defects.…”

Abnormal Neurotransmitter Release Underlying Behavioral and Cognitive Disorders: Toward Concepts of Dynamic and Function-Specific Dysregulation

“…For example, electrically-evoked ACh release from human neocortical slices was demonstrated to decrease with age (Feuerstein and Seeger, 1997). Although the nature of the stimuli used in these studies potentially allow the dissociation of effects of different modes of neuronal activity, the available evidence indicates that overflow data obtained from brain tissues from patients, animals modeling disorders and/or treated with drugs, typically have been interpreted as indicating aberrant tonic levels of neurotransmission (eg, Engler et al, 2006;Roberts et al, 2005).…”