Nectin-3 modulates the structural plasticity of dentate granule cells and long-term memory

Abstract

Nectin-3, a cell adhesion molecule enriched in hippocampal neurons, has been implicated in stress-related cognitive disorders. Nectin-3 is expressed by granule cells in the dentate gyrus (DG), but it remains unclear whether nectin-3 in DG modulates the structural plasticity of dentate granule cells and hippocampus-dependent memory. In this study, we found that DG nectin-3 expression levels were developmentally regulated and reduced by early postnatal stress exposure in adult mice. Most importantly, knockdown of nectin-3 levels in all DG neuron populations by adeno-associated virus (AAV) mimicked the cognitive effects of early-life stress, and impaired long-term spatial memory and temporal order memory. Moreover, AAV-mediated DG nectin-3 knockdown increased the density of doublecortin-immunoreactive differentiating cells under proliferation and calretinin-immunoreactive immature neurons, but markedly decreased calbindin immunoreactivity, indicating that nectin-3 modulates the differentiation and maturation of adult-born DG granule cells. Using retrovirus to target newly generated DG neurons, we found that selective nectin-3 knockdown in new DG neurons also impaired long-term spatial memory. In addition, suppressing nectin-3 expression in new DG neurons evoked a reduction of dendritic spines, especially thin spines. Our data indicate that nectin-3 expressed in DG neurons may modulate adult neurogenesis, dendritic spine plasticity and the cognitive effects of early-life stress.

Postnatal nectin‐3 knockdown induces structural abnormalities of hippocampal principal neurons and memory deficits in adult mice

“…We found that suppression of nectin‐3 in hippocampus from early postnatal stage mimicked early‐life stress effects, impairing novel object recognition that mainly depends on the neuronal network between hippocampus and perirhinal cortex, and spatial object recognition memory which is specifically regulated by the hippocampus (Cohen et al, ; Lupien et al, ). In addition, consistent with other findings, short‐term spatial working memory evaluated by the Y‐maze spontaneous alternation behavior was not significantly altered in mice with nectin‐3 knockdown (Wang et al, , ). These results suggest that nectin‐3 may be partially involved in hippocampus‐dependent memory functions.…”

“…Nectins as CAMs locate at the synaptic sites in neuronal axons and dendrites and play an important role in the formation of synapses by altering the spine number and size which is crucial to learning processes (Mizoguchi et al, ; Takai et al, ; Wang et al, ). Abnormal nectin expression has been observed in stressed mice, which may mediate stress‐induced impairments in hippocampus‐dependent memory and structural plasticity (Liao et al, ; van der Kooij et al ; Wang et al, , ). In the present study, we directly examined the causal involvement of nectins in hippocampal neurodevelopment.…”

“…A growing number of studies suggest that hippocampal nectin‐3 is susceptible to various stress challenges, and is implicated in stress‐induced aberrant neural structure and cognitive dysfunction (Liao et al, ; van der Kooij et al, ; Wang et al, , ). Recently, we reported that early‐life stress resulted in persistent suppression of nectin‐3 expression in hippocampus from postnatal stage (Liao et al, ; Wang et al, ).…”

Precise levels of Nectin-3 and an interaction with Afadin are required for proper synapse formation in postnatal visual cortex

“…Nectin-3 knockdown in adult hippocampus was previously shown to decrease dendritic spine densities relative to control 18,20 . In contrast, we show here that nectin-3 knockdown at E15.5 in L2/3 visual cortical neurons increased dendritic spine densities relative to control at P21, but not at P14 or P35.…”

“…For example, axonal (presynaptic) nectin-1 in dentate granule cells specifically binds to dendritic (postsynaptic) nectin-3 in CA3 principal neurons at the stratum lucidum in hippocampus to help guide and stabilize developing synaptic connections between these neurons ( Figure 1A) 10,14 . Other studies have implicated nectins in a variety of biological and disease states, including long-term memory formation, stress, taopathy, and mental retardation, indicating that nectins may have different functions in the development, aging, and maintenance of various brain circuits [16][17][18][19][20] . While previous work suggests that nectin-1 and nectin-3 may be involved in both the formation and maturation (stabilization) of synapses in hippocampus, their function in postnatal cortical development is unknown 14 .…”