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.

Fyn is a Src-family tyrosine kinase that affects long term potentiation (LTP), synapse formation, and learning and memory. Fyn is also implicated in dendritic spine formation both in vitro and in vivo. However, whether Fyn’s regulation of dendritic spine formation is brain-region specific and age-dependent is unknown. In the present study, we systematically examined whether Fyn altered dendritic spine density and morphology in the cortex and hippocampus and if these effects were age-dependent. We found that Fyn knockout mice trended toward a decrease in dendritic spine density in cortical layers II/III, but not in the hippocampus, at 1 month of age. Additionally, Fyn knockout mice had significantly decreased dendritic spine density in both the cortex and hippocampus at 3 months and 1 year, and Fyn’s effect on dendritic spine density was age-dependent in the hippocampus. Moreover, Fyn knockout mice had wider spines at the three time points (1 month, 3 months, 1 year) in the cortex. These findings suggest that Fyn regulates dendritic spine number and morphology over time and provide further support for Fyn’s role in maintaining proper synaptic function in vivo.

Many Alzheimer' s disease (AD) studies have focused on the synaptotoxic effects of the amyloid β (Aβ) peptide and neglected the possibility that amyloid precursor protein (APP) itself is important for synapse formation and function. We previously demonstrated that APP is highly localized in synapses and is involved in dendritic spine formation. For example, in primary hippocampal neurons in vitro, overexpression of full-length APP promotes the formation of dendritic spines, while knockdown of APP decreases dendritic spine formation [1]. Consistent with these results, dendritic spine density in cortical layers II/III and in the hippocampal CA1 region is reduced in 1-year-old APP knockout (KO) mice [1], and spine formation and spine plasticity in cortical layer V are impaired in 4-month-old APP KO mice [2]. However, the effects of APP on synaptic/cognitive function have not been studied in detail.Recruitment of APP to both pre-and post-synaptic sites is required for synapse formation [3]. In addition, APP is involved in presynaptic vesicle release and postsynaptic N-methyl-D-aspartate receptor (NMDAR) trafficking, indicating a role in synaptic connectivity [4]. Furthermore, overexpression of human APP increases synaptic density, while expression of familial Alzheimer' s disease (FAD)-mutated APP has no effect [5]. Overexpression of