Dendritic Spines in Learning and Memory: From First Discoveries to Current Insights.

The central nervous system is composed of neural ensembles, and their activity patterns are neural correlates of cognitive functions. Those ensembles are networks of neurons connected to each other by synapses. Most neurons integrate synaptic signal through a remarkable subcellular structure called spine. Dendritic spines are protrusions whose diverse shapes make them appear as a specific neuronal compartment, and they have been the focus of studies for more than a century. Soon after their first description by Ramón y Cajal, it has been hypothesized that spine morphological changes could modify neuronal connectivity and sustain cognitive abilities. Later studies demonstrated that changes in spine density and morphology occurred in experience-dependent plasticity during development, and in clinical cases of mental retardation. This gave ground for the assumption that dendritic spines are the particular locus of cerebral plasticity. With the discovery of synaptic long-term potentiation, a research program emerged with the aim to establish whether dendritic spine plasticity could explain learning and memory. The development of live imaging methods revealed on the one hand that dendritic spine remodeling is compatible with learning process and, on the other hand, that their long-term stability is compatible with lifelong memories. Furthermore, the study of the mechanisms of spine growth and maintenance shed new light on the rules of plasticity. In behavioral paradigms of memory, spine formation or elimination and morphological changes were found to correlate with learning. In a last critical step, recent experiments have provided evidence that dendritic spines play a causal role in learning and memory.

Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome.

Rare genetic variants in ANK2, which encodes ankyrin-B, are associated with neurodevelopmental disorders (NDDs); however, their pathogenesis is poorly understood. We find that mice with prenatal deletion in cortical excitatory neurons and oligodendrocytes (Ank2-/-:Emx1-Cre), but not with adolescent deletion in forebrain excitatory neurons (Ank2-/-:CaMKIIα-Cre), display severe spontaneous seizures, increased mortality, hyperactivity, and social deficits. Calcium imaging of cortical slices from Ank2-/-:Emx1-Cre mice shows increased neuronal calcium event amplitude and frequency, along with network hyperexcitability and hypersynchrony. Quantitative proteomic analysis of cortical synaptic membranes reveals upregulation of dendritic spine plasticity-regulatory proteins and downregulation of intermediate filaments. Characterization of the ankyrin-B interactome identifies interactors associated with autism and epilepsy risk factors and synaptic proteins. The AMPA receptor antagonist, perampanel, restores cortical neuronal activity and partially rescues survival in Ank2-/-:Emx1-Cre mice. Our findings suggest that synaptic proteome alterations resulting from Ank2 deletion impair neuronal activity and synchrony, leading to NDDs-related behavioral impairments.

Multiple genes in a single GWAS risk locus synergistically mediate aberrant synaptic development and function in human neurons.

The mechanistic tie between genome-wide association study (GWAS)-implicated risk variants and disease-relevant cellular phenotypes remains largely unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons as a neurodevelopmental model, we identify multiple schizophrenia (SZ) risk variants that display allele-specific open chromatin (ASoC) and are likely to be functional. Editing the strongest ASoC SNP, rs2027349, near vacuolar protein sorting 45 homolog (VPS45) alters the expression of VPS45, lncRNA AC244033.2, and a distal gene, C1orf54. Notably, the transcriptomic changes in neurons are associated with SZ and other neuropsychiatric disorders. Neurons carrying the risk allele exhibit increased dendritic complexity and hyperactivity. Interestingly, individual/combinatorial gene knockdown shows that these genes alter cellular phenotypes in a non-additive synergistic manner. Our study reveals that multiple genes at a single GWAS risk locus mediate a compound effect on neural function, providing a mechanistic link between a non-coding risk variant and disease-related cellular phenotypes.

Intercellular signaling by ectodomain shedding at the synapse.

Ectodomain shedding (ES) is a post-translational protein modification process that plays key roles in health and disease. Many neuronal and synaptic membrane proteins are known to undergo ES, but the complexity of functions regulated by the shed peptides is only beginning to be unraveled. Here, we provide an overview of emerging evidence demonstrating that synaptic ES can mediate autocrine and paracrine signaling. We also discuss how advances in large-scale proteomic analyses are leading to the identification of novel synaptic proteins undergoing ES, as well as the targets and functions of their soluble ectodomains. Finally, we provide an overview of how cerebrospinal fluid (CSF) analyses of shed proteins could be used as a potential source of new biomarkers for neuropsychiatric disorders.