Soluble β-amyloid (Aβ) oligomers impair synaptic plasticity and cause synaptic loss associated with Alzheimer’s disease (AD). We report that murine PirB (paired immunoglobulin-like receptor B) and its human ortholog LilrB2 (leukocyte immunoglobulin-like receptor B2), present in human brain, are receptors for Aβ oligomers, with nanomolar affinity. The first two extracellular immunoglobulin (Ig) domains of PirB and LilrB2 mediate this interaction, leading to enhanced cofilin signaling, also seen in human AD brains. In mice, the deleterious effect of Aβ oligomers on hippocampal long-term potentiation required PirB, and in a transgenic model of AD, PirB not only contributed to memory deficits present in adult mice, but also mediated loss of synaptic plasticity in juvenile visual cortex. These findings imply that LilrB2 contributes to human AD neuropathology and suggest therapeutic uses of blocking LilrB2 function.

Experience-driven circuit changes underlie learning and memory. Monocular deprivation (MD) engages synaptic mechanisms of ocular dominance (OD) plasticity and generates robust increases in dendritic spine density on L5 pyramidal neurons. Here we show that the paired immunoglobulin-like receptor B (PirB) negatively regulates spine density, as well as the threshold for adult OD plasticity. In PirB −/− mice, spine density and stability are significantly greater than WT, associated with higher-frequency miniature synaptic currents, larger long-term potentiation, and deficient long-term depression. Although MD generates the expected increase in spine density in WT, in PirB −/− this increase is occluded. In adult PirB −/− , OD plasticity is larger and more rapid than in WT, consistent with the maintenance of elevated spine density. Thus, PirB normally regulates spine and excitatory synapse density and consequently the threshold for new learning throughout life.visual cortex | adult plasticity |

Visual Abstract

Architectonic heterogeneity in neurons is thought to be important for equipping the mammalian cerebral cortex with an adaptable network that can organize the manifold totality of information it receives. To this end, the dendritic arbors of supragranular pyramidal neurons, even those of the same class, are known to vary substantially. This diversity of dendritic morphology appears to have a rostrocaudal configuration in some brain regions of various species. For example, in humans and non-human primates, neurons in more rostral visual association areas (e.g., V4) tend to have more complex dendritic arbors than those in the caudal primary visual cortex. A rostrocaudal configuration is not so clear in any region of the mouse, which is increasingly being used as a model for neurodevelopmental disorders that arise from dysfunctional cerebral cortical circuits. Therefore, in this study we investigated the complexity of dendritic arbors of neurons distributed throughout a broad area of the mouse cerebral cortex. We reduced selection bias by labeling neurons restricted to become supragranular pyramidal neurons using in utero electroporation. While we observed that the simple rostrocaudal position, cortical depth, or even functional region of a neuron was not directly related to its dendritic morphology, a model that instead included a caudomedial-to-rostrolateral gradient accounted for a significant amount of the observed dendritic morphological variance. In other words, rostrolateral neurons from our data set were generally more complex when compared to caudomedial neurons. Furthermore, dividing the cortex into a visual area and a non-visual area maintained the power of the relationship between caudomedial-to-rostrolateral position and dendritic complexity. Our observations therefore support the idea that dendritic morphology of mouse supragranular excitatory pyramidal neurons across much of the tangential plane of the cerebral cortex is partly shaped by a developmental gradient spanning several functional regions.