About Our Work

For a person to think, act, or feel, the neurons in a person’s brain must communicate continuously, rapidly, and repeatedly. This communication occurs at synapses, specialized junctions that allow neurons to exchange information on a millisecond timescale and that organize neurons into vast overlapping circuits.

Our laboratory studies how synapses form in the brain, how their properties are specified, and how they accomplish the rapid and precise signaling that forms the basis for all information processing by the brain. The establishment and specification of synapses, their properties and plasticity determine the input-output relations of neural circuits, and thus underlie all brain function. Moreover, increasing evidence links impairments in synaptic transmission to disorders such as Alzheimer’s diseases, schizophrenia, and autism. Thus, our laboratory also aims to contribute to the understanding of neuropsychiatric and neurodegenerative disorders.

Trans-synaptic network 

Interactions of candidate trans-synaptic adhesion molecules. The indicated molecules form vast molecular interaction networks that are thought to control the establishment and specification of synapses as well as various forms of synaptic plasticity. Modified from Südhof, Neuron 2018

Synapse formation

The goal of our work on synapse formation is to understand the molecular determinants that shape the function of synapses as the fundamental information processing units in neural circuits, with the overall aim of defining the molecular logic that constructs these circuits. Synapses exhibit a high degree of specificity. Neurons form synapses with only a select subset of other neurons, and the resulting synaptic connections exhibit an astounding diversity of properties that are specified by the pre- and postsynaptic neurons. Our laboratory is focusing on synaptic cell-adhesion molecules that form a dynamic network across the synaptic cleft to control for establishment and specification of synaptic connections between neurons. In addition, we are analyzing secreted synaptogenic molecules produced by neurons and glia or circulating in the blood that promote synapse formation and synaptic transmission.

Lphn-teneurin & -FLRT interactions

Different isoforms of latrophilins (Lphn2 and Lphn3) are specifically targeted to distinct dendritic domains of pyramidal neurons in the CA1 region of the hippocampus, where the latrophilins are instrumental in establishing synapses formed by specific presynaptic axons emanating from the CA3 region or the entorhinal cortex. Modified from Sando et al., Science 2019.

Synaptic adhesion molecules

In examining synapse formation, our laboratory is studying a range of key synaptic adhesion molecules, such as neurexins, neuroligins, teneurins, Bai's and latrophilins. Together these adhesion molecules with their many intra- and extracellular binding partners make and shape synapses. They dictate the establishment of synapses, render synapses functional, and endow synapses with specific properties, such as the ability to undergo long-term potentiation. At present, we as neuroscientists do not understand how synapses are made, we do know why some synapses are competent to engage in long-term plasticity and others are not, and how the properties of synapses are specified. We hypothesize that all of these processes are controlled by signaling via synaptic adhesion molecules, and have obtained accumulating evidence in support of this hypothesis. 

In recent work, we discovered among others that specific splice variants of presynaptic neurexins instruct the postsynaptic glutamate receptor composition and enable postsynaptic spines to undergo LTP (Aoto et al., 2013; Dai et al., 2019). Furthermore, we found that at specific subsets of hippocampal synapses, different isoforms of latrophilins, postsynaptic adhesion-GPCRs, are essential for the formation of synapses by interacting with presynaptic teneurins and FLRTs (Sando et al., 2019). These examples illustrate the challenge we face: to deconvolve into simple individual processes the overall complex mechanism by which synaptic connections construct functional neural circuits. Moreover, mutations in neurexins and their 

Model of transsynaptic signaling by Nrxn3alpha and dystroglycan at inhibitory synapses in the prefrontal cortex and olfactory bulbModel of transsynaptic signaling by Nrxn3alpha and dystroglycan at inhibitory synapses in the prefrontal cortex and olfactory bulb

Summary cartoon illustrates the complex between presynaptic Nrxn3alpha and postsynaptic dystroglycan and Neuroligin-2 and -3 (Nlgn2/3) that is essential for normal synaptic transmission but not required for synapse formation. Binding of presynaptic Nrxn3 to postsynaptic dystroglycan is regulated by alternative splicing as outlined in the Nrxn3 splice code table on the right. Nrxn3 binds to dystroglycan via its LNS2 and LNS6 domains that are both alternatively spliced, such that either exclusion of the alternatively spliced LNS2 (SS2) or LNS6 sequence (SS4) is sufficient to activate binding. Upon binding, postsynaptic dystroglycan signals back to the presynaptic terminal to increase the presynaptic release probability (PR) (Trotter et al., Nature Comm. in press). 

ligands, chiefly neuroligins, are observed in autism spectrum disorders and in schizophrenia, suggesting that their role in shaping synaptic communication is impaired in these diseases. These mutations are physiologically significant, as we demonstrated using both isogenic engineered human neurons as well as patient-derived human neurons. 

Synaptotrophic signaling molecules

In addition to trans-synaptic adhesion molecules, proteins secreted by astrocytes or the choroid plexus, or proteins entering the brain from the systemic circulation, promote synapse formation by binding to specific cell-surface receptors. Such proteins include ApoE, SPARCL1, and thrombospondins. We are examining how these proteins work, and how their actions relate to aging and to neurodegenerative disorders such as Alzheimer’s disease. Understanding these proteins as metaplastic modulators of neural circuits will be essential to gain insight into how the brain’s circuits change as a function of environmental or pathogenic challenges. . 

Synapse modifications in memory

Long-term memories are thought to be mediated by changes in synapse numbers and synapse properties in defined neural circuits. How these changes are effected,  however, remains unclear. Our laboratory is using our expertise in the molecular definition of synapses and in monitoring synaptic connections for a better understanding of how synapse modifications mediate learning and memory. Our focus here is not on specific circuits, but on defining the molecular changes that are generally required for learning long-term memories and how they relate to synapses, using again a broad range of techniques that include single-cell RNAseq, imaging, behavior, and protein chemistry.

The Pathobiology of Synapses in neurodegenerative disorders

In extension of our work on synapses, we also examine how neurodegenerative disorders cause a loss of synapses. Here, we focus on ApoE and on APP, two proteins that are genetically linked to Alzheimer’s disease and other neurodegenerative disorders. ApoE is involved in lipid transport, but the relation of lipid transport to synapse formation and Alzheimer’s disease remains unclear and is a focus of our work. Despite decades of work, APP’s physiological and pathological roles remain incompletely understood, but APP has also been implicated in synaptic functions. Elucidating how ApoE and APP function at the synapse physiologically and how ther role at the synapse relates to neurodegenerative disorders thus is another general focus of our work.

Methods and approaches

To study synapses and their impairments in disease, we use a highly interdisciplinary approach that combines structural biology, mouse genetics, electrophysiology with optical imaging and behavior. We employ mice and human neurons trans-differentiated from stem cells as model systems. Our work is carried out in close collaborations with colleagues at Stanford and elsewhere, with the overall goal to not only describe how a neural circuit processes information, but to understand the underlying molecular events such explain information processing.

Weekly Subgroup Meetings

ApoE, etc: Everything Relating to Neurodegeneration

Screens & Tools: From Purified Complexes to Complex Behaviors

Neurexins Subgroup

Adhesion Molecules in Synapse Formation (Except for Neurexins)