A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts.

Junctions between the ER and plasma membrane (PM) are implicated in calcium homeostasis, non-vesicular lipid transfer, and other cellular functions. Two ER proteins that function both as tethers to the PM via a polybasic C-terminus motif and as phospholipid transporters are brain-enriched TMEM24 (C2CD2L) and its paralog C2CD2. We report that both proteins also form a complex with band 4.

Transient impairment in microglial function causes sex-specific deficits in synaptic maturity and hippocampal function in mice exposed to early adversity.

Abnormal development and function of the hippocampus are two of the most consistent findings in humans and rodents exposed to early-life adversity (ELA), with males often being more affected than females. Using the limited bedding (LB) paradigm as a rodent model of ELA, we found that male adolescent mice that had been exposed to LB exhibit significant deficits in contextual fear conditioning and synaptic connectivity in the hippocampus, which are not observed in females. This is linked to altered developmental refinement of connectivity, with LB severely impairing microglial-mediated synaptic pruning in the hippocampus of male and female pups on postnatal day 17 (P17), but not in adolescent P33 mice when levels of synaptic engulfment by microglia are substantially lower.

A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts.

Junctions between the ER and the plasma membrane (ER/PM junctions) are implicated in calcium homeostasis, non-vesicular lipid transfer and other cellular functions. Two ER proteins that function both as membrane tethers to the PM via a polybasic motif in their C-terminus and as phospholipid transporters are brain-enriched TMEM24 (C2CD2L) and its paralog C2CD2. Based on an unbiased proximity ligation analysis, we found that both proteins can also form a complex with band 4.

The human milk component -inositol promotes neuronal connectivity.

Effects of micronutrients on brain connectivity are incompletely understood. Analyzing human milk samples across global populations, we identified the carbocyclic sugar -inositol as a component that promotes brain development. We determined that it is most abundant in human milk during early lactation when neuronal connections rapidly form in the infant brain.

CADM2 is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice.

Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders. We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N = 123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N = 130,684). Because these GWAS implicated the gene CADM2, we next performed single-SNP phenome-wide studies (PheWAS) of several of the implicated variants in CADM2 in a multi-ancestral 23andMe cohort (N = 3,229,317, European; N = 579,623, Latin American; N = 199,663, African American).

Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions.

Multiple trans-synaptic complexes organize synapse development, yet their roles in the mature brain and cooperation remain unclear. We analyzed the postsynaptic adhesion protein LRRTM1 in the prefrontal cortex (PFC), a region relevant to cognition and disorders. LRRTM1 knockout (KO) mice had fewer synapses, and we asked whether other synapse organizers counteract further loss.

A synaptomic analysis reveals dopamine hub synapses in the mouse striatum.

Dopamine transmission is involved in reward processing and motor control, and its impairment plays a central role in numerous neurological disorders. Despite its strong pathophysiological relevance, the molecular and structural organization of the dopaminergic synapse remains to be established. Here, we used targeted labelling and fluorescence activated sorting to purify striatal dopaminergic synaptosomes.

Subsynaptic positioning of AMPARs by LRRTM2 controls synaptic strength.

Recent evidence suggests that nano-organization of proteins within synapses may control the strength of communication between neurons in the brain. The unique subsynaptic distribution of glutamate receptors, which cluster in nanoalignment with presynaptic sites of glutamate release, supports this hypothesis. However, testing it has been difficult because mechanisms controlling subsynaptic organization remain unknown.

Three-dimensional adaptive optical nanoscopy for thick specimen imaging at sub-50-nm resolution.

Understanding cellular organization demands the best possible spatial resolution in all three dimensions. In fluorescence microscopy, this is achieved by 4Pi nanoscopy methods that combine the concepts of using two opposing objectives for optimal diffraction-limited 3D resolution with switching fluorescent molecules between bright and dark states to break the diffraction limit. However, optical aberrations have limited these nanoscopes to thin samples and prevented their application in thick specimens.

Synaptic recognition molecules in development and disease.

Synaptic connectivity patterns underlie brain functions. How recognition molecules control where and when neurons form synapses with each other, therefore, is a fundamental question of cellular neuroscience. This chapter delineates adhesion and signaling complexes as well as secreted factors that contribute to synaptic partner recognition in the vertebrate brain.

FARP-1 deletion is associated with lack of response to autism treatment by early start denver model in a multiplex family.

Background: Children with autism spectrum disorder (ASD) display impressive clinical heterogeneity, also involving treatment response. Genetic variants can contribute to explain this large interindividual phenotypic variability.

Methods: Array-CGH (a-CGH) and whole genome sequencing (WGS) were performed on a multiplex family with two small children diagnosed with ASD at 17 and 18 months of age.

Emerging Roles of Synapse Organizers in the Regulation of Critical Periods.

Experience remodels cortical connectivity during developmental windows called critical periods. Experience-dependent regulation of synaptic strength during these periods establishes circuit functions that are stabilized as critical period plasticity wanes. These processes have been extensively studied in the developing visual cortex, where critical period opening and closure are orchestrated by the assembly, maturation, and strengthening of distinct synapse types.

SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse.

Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes.

Synaptic Connectivity and Cortical Maturation Are Promoted by the ω-3 Fatty Acid Docosahexaenoic Acid.

Brain development is likely impacted by micronutrients. This is supported by the effects of the ω-3 fatty acid docosahexaenoic acid (DHA) during early neuronal differentiation, when it increases neurite growth. Aiming to delineate DHA roles in postnatal stages, we selected the visual cortex due to its stereotypic maturation.

Synapse-Selective Control of Cortical Maturation and Plasticity by Parvalbumin-Autonomous Action of SynCAM 1.

Cortical plasticity peaks early in life and tapers in adulthood, as exemplified in the primary visual cortex (V1), wherein brief loss of vision in one eye reduces cortical responses to inputs from that eye during the critical period but not in adulthood. The synaptic locus of cortical plasticity and the cell-autonomous synaptic factors determining critical periods remain unclear. We here demonstrate that the immunoglobulin protein Synaptic Cell Adhesion Molecule 1 (SynCAM 1/Cadm1) is regulated by visual experience and limits V1 plasticity.

Mapping the Proteome of the Synaptic Cleft through Proximity Labeling Reveals New Cleft Proteins.

Synapses are specialized neuronal cell-cell contacts that underlie network communication in the mammalian brain. Across neuronal populations and circuits, a diverse set of synapses is utilized, and they differ in their molecular composition to enable heterogenous connectivity patterns and functions. In addition to pre- and post-synaptic specializations, the synaptic cleft is now understood to be an integral compartment of synapses that contributes to their structural and functional organization.

Social Stimulus Causes Aberrant Activation of the Medial Prefrontal Cortex in a Mouse Model With Autism-Like Behaviors.

Autism spectrum disorder (ASD) is a highly prevalent and genetically heterogeneous brain disorder. Developing effective therapeutic interventions requires knowledge of the brain regions that malfunction and how they malfunction during ASD-relevant behaviors. Our study provides insights into brain regions activated by a novel social stimulus and how the activation pattern differs between mice that display autism-like disabilities and control littermates.

Structural analyses of FERM domain-mediated membrane localization of FARP1.

FARP1 is a multi-domain protein that is involved in regulating neuronal development through interacting with cell surface proteins such as class A Plexins and SynCAM 1. The N-terminal FERM domain in FARP1 is known to both promote membrane localization and mediate these protein interactions, for which the underlying molecular mechanisms remain unclear. Here we determined the crystal structures of the FERM domain of FARP1 from zebrafish, and those of FARP2 (a close homolog of FARP1) from mouse and zebrafish.

Open Up to Make New Contacts: Caldendrin Senses Postsynaptic Calcium Influx to Dynamically Organize Dendritic Spines.

In this issue of Neuron, Mikhaylova et al. (2018) report how the Ca sensor caldendrin interacts in dendritic spines with cortactin to control actin remodeling. Combining molecular and functional approaches, this work gains insights into postsynaptic dynamics relevant for synaptic plasticity.

Transcellular Nanoalignment of Synaptic Function.

At each of the brain's vast number of synapses, the presynaptic nerve terminal, synaptic cleft, and postsynaptic specialization form a transcellular unit to enable efficient transmission of information between neurons. While we know much about the molecular machinery within each compartment, we are only beginning to understand how these compartments are structurally registered and functionally integrated with one another. This review will describe the organization of each compartment and then discuss their alignment across pre- and postsynaptic cells at a nanometer scale.

Reduced Insulin/Insulin-Like Growth Factor Receptor Signaling Mitigates Defective Dendrite Morphogenesis in Mutants of the ER Stress Sensor IRE-1.

Neurons receive excitatory or sensory inputs through their dendrites, which often branch extensively to form unique neuron-specific structures. How neurons regulate the formation of their particular arbor is only partially understood. In genetic screens using the multidendritic arbor of PVD somatosensory neurons in the nematode Caenorhabditis elegans, we identified a mutation in the ER stress sensor IRE-1/Ire1 (inositol requiring enzyme 1) as crucial for proper PVD dendrite arborization in vivo.

Excitatory Synaptic Drive and Feedforward Inhibition in the Hippocampal CA3 Circuit Are Regulated by SynCAM 1.

Unlabelled: Select adhesion proteins control the development of synapses and modulate their structural and functional properties. Despite these important roles, the extent to which different synapse-organizing mechanisms act across brain regions to establish connectivity and regulate network properties is incompletely understood. Further, their functional roles in different neuronal populations remain to be defined.

How a Piggyback Synapse Listens in to Tune Excitatory Terminals.

In this issue of Neuron, Mende et al. (2016) report how axo-axonic synapses of interneurons balance the strength of glutamatergic terminals in the spinal cord. The results highlight presynaptic roles of mGluR1 receptors and of BDNF as a retrograde signal to regulate GABA synthesis and tune transmission.

Topographic Mapping of the Synaptic Cleft into Adhesive Nanodomains.

The cleft is an integral part of synapses, yet its macromolecular organization remains unclear. We show here that the cleft of excitatory synapses exhibits a distinct density profile as measured by cryoelectron tomography (cryo-ET). Aiming for molecular insights, we analyzed the synapse-organizing proteins Synaptic Cell Adhesion Molecule 1 (SynCAM 1) and EphB2.