ABSTRACT
The lipoprotein receptor ligand Reelin is important for the processes of normal synaptic plasticity, dendritic morphogenesis, and learning and memory. Heterozygous reeler mice (HRM) show many neuroanatomical, biochemical, and behavioral features that are associated with schizophrenia. HRM show subtle morphological defects including reductions in dendritic spine density, altered synaptic plasticity and behavioral deficits in associative learning and memory and pre-pulse inhibition. The present studies test the hypothesis that in vivo elevation of Reelin levels can rescue synaptic and behavioral phenotypes associated with HRM. We demonstrate that a single in vivo injection of Reelin increases GAD67 expression and alters dendritic spine morphology. In parallel we observed enhancement of hippocampal synaptic function and associative learning and memory. Reelin supplementation also increases pre-pulse inhibition. These results suggest that characteristics of HRM, similar to those observed in schizophrenia, are sensitive to Reelin levels and can be modified with Reelin supplementation in male and female adults.
Subject(s)
Cell Adhesion Molecules, Neuronal/metabolism , Extracellular Matrix Proteins/metabolism , Gait Disorders, Neurologic/metabolism , Learning Disabilities/metabolism , Nerve Tissue Proteins/metabolism , Neuronal Plasticity , Schizophrenia/metabolism , Serine Endopeptidases/metabolism , Animals , Cell Adhesion Molecules, Neuronal/genetics , Crosses, Genetic , Dendritic Spines/metabolism , Dendritic Spines/pathology , Extracellular Matrix Proteins/genetics , Female , Gait Disorders, Neurologic/etiology , Glutamate Decarboxylase/metabolism , Heterozygote , Hippocampus/metabolism , Learning , Learning Disabilities/etiology , Male , Mice , Mice, Neurologic Mutants , Nerve Tissue Proteins/genetics , Neural Inhibition , Neurons/metabolism , Reelin Protein , Schizophrenia/pathology , Schizophrenia/physiopathology , Sensory Gating , Serine Endopeptidases/genetics , Synaptic TransmissionABSTRACT
Apolipoprotein receptors belong to an evolutionarily conserved surface receptor family that has intimate roles in the modulation of synaptic plasticity and is necessary for proper hippocampal-dependent memory formation. The known lipoprotein receptor ligand Reelin is important for normal synaptic plasticity, dendritic morphology, and cognitive function; however, the in vivo effect of enhanced Reelin signaling on cognitive function and synaptic plasticity in wild-type mice is unknown. The present studies test the hypothesis that in vivo enhancement of Reelin signaling can alter synaptic plasticity and ultimately influence processes of learning and memory. Purified recombinant Reelin was injected bilaterally into the ventricles of wild-type mice. We demonstrate that a single in vivo injection of Reelin increased activation of adaptor protein Disabled-1 and cAMP-response element binding protein after 15 min. These changes correlated with increased dendritic spine density, increased hippocampal CA1 long-term potentiation (LTP), and enhanced performance in associative and spatial learning and memory. The present study suggests that an acute elevation of in vivo Reelin can have long-term effects on synaptic function and cognitive ability in wild-type mice.
