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7.342 | Fall 2022 | Undergraduate

# Synapse Remodeling in Health and Disease

Each lecture summary is based on the corresponding readings for that week.

Week | Topics | Lecture Summaries
--- | --- | ---
1 | Introduction | This first class will be an introduction to the course, instructors, and students. We will begin by introducing ourselves and our research backgrounds and interests. Students will be invited to share their interests and what they hope to get out of the course. We will describe the syllabus, goals, and expectations for the course and schedule meeting times. The instructors will provide a broad overview of key techniques used in papers throughout the course, methods for efficient primary literature search (including PubMed and Google Scholar), and a brief introduction to the subjects we will focus on for the rest of the semester and, in particular, to the two papers to be covered next week.
2 | Synapse Plasticity: Developing Brain | Neural circuit organization and reorganization begin during embryonic development and continue into adulthood. At birth, our brains are packed with more than 100 billion (1011) neurons (Ackerman, 1992)* continuously talking to each other via their synaptic connections. This network of neurons is wired excessively to ensure we have enough connections to circulate information through specific brain regions to carry out specific tasks. As we learn and grow, our experiences strengthen certain connections, while others weaken and fade. This process is called “synaptic pruning” and involves the active removal of synaptic connections as part of the process that creates a network of synaptic connections tuned to our experiences. In the 1970s, the neurologist Peter Huttenlocher counted synapses in electron micrographic high-resolution images of postmortem human brains ranging from a newborn to a 90-year-old. He showed that synaptic density in the human cerebral cortex increases rapidly after birth, peaking at 1 to 2 years of age, dropping sharply during adolescence, and then stabilizing in adulthood, with a slight possible decline late in life (Huttenlocher, 1979)**. His observations revealed that the brain matures at different stages in different brain regions. These studies offered a static view of synapse numbers at different ages—postmortem tissue cannot indicate how synapses are being removed and reassembled at different ages, i.e. cannot provide a dynamic picture of structural plasticity across development. To investigate synaptic structural plasticity, neuroscientists turned to animal models to visualize individual connections in living tissue, revealing what happens to specific brain regions and circuits during normal development. This week we will focus on limbic circuitry, which is important for emotion and decision-making, and learn about the distinctive patterns of neuronal connection, plasticity, and stability of the network before and after adolescence. Using Johnson et al. (2016), we will discuss synaptic plasticity in the context of synaptic pruning in long-range projections from the amygdala and orbitofrontal cortex (OFC), regions involved in processing emotions and making decisions. Counotte et al. (2010) dive into the world of individual synapses and learn about how distinctive protein content can distinguish immature and mature synaptic connections. *Ackerman, S. Discovering the Brain. Washington (DC): National Academies Press (US); 1992. “6, The Development and Shaping of the Brain.” Available from: https://www.ncbi.nlm.nih.gov/books/NBK234146/ **Huttenlocher, PR. “Synaptic density in human frontal cortex - developmental changes and effects of aging.” Brain Res. 1979 Mar 16;163(2):195-205. doi: 10.1016/0006-8993(79)90349-4. PMID: 427544.
3 | Synapse Plasticity: Aging Brain | One may imagine that as we get older, our brain cells also get older and start to die. However, multiple lines of evidence have shown that loss of brain cells caused by cell death is quite limited during normal aging and unlikely to account for all age-related neurological impairments. Rather, it seems that structural alterations in neuronal morphology and synaptic connections are features most consistently correlated with brain age and are candidates to define the physical basis of age-related functional cognitive decline, which often include deficits in memory retention and processing as well as in sensory information processing. This week we will discuss Mostany et al. (2013) to learn about the morphological changes that dendritic spines and synapses undergo as a neuron ages. Using in vivo imaging and spine reconstruction, they show that age-related decline is associated with alterations in the size and stability of spines and boutons rather than cell loss. Using Eavri et al. (2018), we will explore how these morphological changes in structural connections affect inhibitory circuitry and lead to reduced capacity for circuit-level plasticity in response to visual stimulation.
4 | Sensory Experience-Dependent Plasticity—Part 1 | In the last couple of weeks, we have learned how excitatory and inhibitory components of cortical circuitry are remodeled in the healthy brain during adolescence and aging. Synapses are also remodeled in response to life experiences, including changes in sensory input. Extensive studies of the mouse visual system, a rich and well-characterized brain region that provides an experimental toolkit for manipulating experience, have revealed both functional and structural plasticity in response to changes in visual experience. This week, we explore remodeling of both excitatory and inhibitory synapses in the mouse primary visual cortex in response to visual manipulation. From van Versendaal et al. (2012), we will get a first glimpse at the structural dynamics of inhibitory postsynaptic sites in response to visual deprivation. Historical data has primarily analyzed remodeling of dendritic spines, which house excitatory synapses, but we knew little about the remodeling of inhibitory synapses in vivo. Using a novel genetic labeling approach to visualize inhibitory synapses in vivo, van Versendaal et al. (2012) show that inhibitory synapses are lost in response to deprivation of visual input from one eye. We will then discuss how Tan et al. (2020) used a similar method to longitudinally monitor the expression of synaptic AMPA receptors (AMPARs), which are the major neuronal receptors used in facilitating excitatory synaptic transmission, across multiple cortical layers in awake mice. They find that changes in synaptic AMPARs expression are depth-dependent—deep synapses are potentiated more than superficial synapses, which results in increased clustering of AMPARs at the surface to mediate synaptic transmission.
5 | Sensory Experience-Dependent Plasticity—Part 2 | Our current notion of how to identify a stable and mature new spine is based on the presence or absence of specific protein markers that are linked to synaptic transmission. Two important and interconnected steps in synapse maturation are the accumulation of the scaffolding molecule PSD-95 and the recruitment of AMPA-type glutamate receptors to the postsynaptic membrane. While multiple molecules have been implicated in the emergence of pre- and postsynaptic structures, little is known about how these molecules trigger the specific steps that lead to synapse stabilization and maturation. The rodent barrel cortex, where inputs corresponding to individual whiskers are spatially segregated in barrels in layer 4 of the barrel cortex and with defined borders between barrel columns, provides an excellent paradigm to study the functional significance of activity-dependent plasticity in the stabilization of spines. This week’s readings will focus on the proteins involved in the stabilization of newly formed spines in the context of experience-dependent circuit plasticity. Wilbrecht et al. (2010) show that whisker potentiation and spine stabilization are most pronounced at the border between spared and deprived barrel columns of normal mice. Mice carrying the CaMKII-T286A mutation lack experience-dependent potentiation of responses to spared whiskers and show no increase in new spine stabilization at the border between barrel columns after whisker trimming, providing further evidence that CaMKII plays a role in the stabilization but not the formation of new spines. Using a similar paradigm, Seaton et al. (2020) provide further evidence that sensory manipulation induces both functional and structural plasticity, including the enlargement of existing spines and the formation of new spines that persist for weeks.
6 | Learning-Induced Synaptic Plasticity | Learning and memory are critical functions that allow animals, including humans, to alter behaviors in the face of changing environments. Learned behaviors are essentially a record left in your brain in the form of modified connections between neurons. Such modifications reflect a process known as learning-induced plasticity. Learning-based changes are measured in the brain by the gain and loss of individual synapses in specific brain regions that are involved in the task being learned. This week, we explore synaptic changes associated with learning. In Johnson et al*.* (2016), we will focus on learning-induced gain and loss of boutons, which represent the pre-synaptic side of synapses, on long-range axons projecting from the orbitofrontal cortex (OFC) to dorsomedial prefrontal cortex (dmPFC), both regions implicated in rule learning. Johnson et al. (2016) show that learning a decision-making task modifies synaptic connections between OFC and dmPFC. With Roth et al*.* (2020), we will explore learning-based plasticity at the molecular level by focusing on the trafficking of individual proteins at excitatory postsynaptic sites. Roth et al. (2020) show that motor learning induces cortical synaptic potentiation by increasing the net trafficking of AMPA receptors into spines. We will also discuss the advantages and limitations of these different ways of measuring synaptic changes.
7 | Neurodevelopmental Disorders: Autism and Fragile X Syndrome | Neurodevelopmental disorders are a group of conditions that affect how the brain functions and arise from abnormalities in brain growth and development. Symptoms of these disorders range from mild impairments that allow for normal life to severe malfunctions that require extensive care. During development, there are many crucial time windows during which different behaviors are especially susceptible to or require a specific environmental influence to develop normally. Such windows, known as critical periods of plasticity, are periods during which specific brain circuits are sculpted by environmental cues or life experiences to become mature and efficient networks. Circuit malformation can lead to synaptic wiring deficits and perturbed brain function, i.e. in neurodevelopmental disorders. Autism spectrum disorders (ASDs) and Fragile X syndrome (FXS) provide examples of neurodevelopmental disorders. ASDs impact a child’s ability to speak, process emotions, and behave appropriately, and create deficits in learning and memory. Similarly, FXS presents cognitive deficits via impaired cognitive flexibility. Such deficits usually show up early in a child’s development, often before the child enters elementary school, and can continue throughout the individual’s lifetime. As the etiology of these disorders remains elusive, neurodevelopmental disorders continue to be defined only by symptoms, which can vary depending on the severity and complexity of each individual case. To identify the molecular and cellular mechanisms underlying ASDs, scientists have created animal models by introducing genetic defects equivalent to those detected in patients. This week, we will first explore Arroyo et al. (2019) and discuss how animal studies have revealed important dysfunctions in synaptic signaling associated with behavioral deficits reflective of those found in autistic children. We will then discuss Krueger et al. (2011) to determine the molecular and cellular consequences of fmr1 gene deletion, a gene associated with FXS in synaptic plasticity, by analyzing synaptic proteomic content in neurons of mice lacking the fmr1 gene.
8 | Workshop Mock Grant Proposals Rough draft of mock grant proposal due | The ability to attain funding is an essential and invaluable skill for a career in STEM in both academia and industry. Individual fellowship and grant proposals have a specific format for writing, which varies depending on individual grant requirements. This week we will work together to critique the draft proposals you have prepared and will provide constructive criticism to help improve your ability to write a grant proposal. This discussion will consider various alternative perspectives about and styles of grant writing to help you identify and solidify your own style. Your draft grant proposal must include a background section to provide context for your proposed research question, details about the question you are asking and your hypothesis, proposed experiments and controls, and a brief description of the expected outcomes of the project (see “Written Assignment” in Assignments section for more detail). This activity should help students in evaluating and editing their own draft proposals to successfully generate a strong final grant proposal. The skills attained during this session should be applicable to any STEM field and multiple funding sources, such as the National Science Foundation Graduate Research Program, which provides fellowships for upcoming and first-year graduate students.
9 | Neurodegeneration: Alzheimer’s Disease Final draft of mock grant proposal due | Proteins serve as the workhorses of neuronal cell function. The process of protein homeostasis, also known as proteostasis, involves an extensive network of cellular components that maintain cellular health by regulating protein synthesis, folding, transport and degradation and limit the accumulation of abnormal protein aggregates. Proteostasis is essential to regulate the proteins that act together to maintain pre- and postsynaptic connections and regulate synaptic transmission and spine removal, all critical for the survival and maturation of synaptic connections. When proteostasis fails, protein misfolding can occur and lead to protein aggregation and abnormal accumulation of harmful inclusions. Abnormal accumulation of the amyloid beta peptide (Aβ) is a histopathological hallmark of Alzheimer’s disease (AD). Aβ is derived from the amyloid beta precursor protein (APP), a protein responsible for proper neuronal growth and repair. In Lesne et al. (2006), we will first explore the amyloid cascade hypothesis, which dictates that excess or inappropriately processed beta-amyloid is the causative agent of plaque (aggregates of misfolded protein formed in between nerve cells) formation, which in turn is the cause of downstream pathologies such as tau tangles (abnormal accumulation of the microtubule protein tau inside neurons) and synapse loss that result in dementia. Lesne et al. explore the amyloid hypothesis in the context of the effect of Aβ on memory. Using Tg2576 mice, which express a human APP variant associated with AD, they conclude that Aβ aggregation is the cause of memory decline in the absence of neurodegeneration. Despite our understanding of aspects of the pathology, the molecular mechanism that links Aβ protein aggregation to neuronal cell death remains a critical gap in our knowledge. In reading Wu et al. (2010), we will focus on an alternate hypothesis that infers synaptic neurodegeneration might be occurring even before the appearance of amyloid protein aggregates. Wu et al. (2010) show that activation of the calcium-dependent phosphatase calcineurin, even in the absence of Aβ, is sufficient to produce a phenocopy of Aβ-induced dystrophic neurites and dendritic spine loss in both neurons in culture and in the adult mouse brain.
10 | Injury: Peripheral Nerve Injury and Traumatic Brain Injury | Traumatic brain injury (TBI) is a form of brain dysfunction caused by an outside force, such as a violent blow to the head, car accident, or fall, all of which can result in damage to the brain. In the US, TBI is a major cause of morbidity and mortality and affects millions of people. Such traumatic events result in memory loss and, in some cases, physical impairment. This week we will dive into the role of PKR-like ER kinase (PERK), a transmembrane protein residing in the endoplasmic reticulum (ER), as a key sensor of ER stress. Prior research has shown that activated PERK is responsible for memory deficiency, which is the most common problem in TBI patients. Sen et al*.* (2017) show us that blocking the activation of PERK using an inhibitor prevents the loss of dendritic spines and rescues memory deficits after TBI. Similarly, peripheral nerve injury can induce pathological conditions by sending noxious stimulation through the peripheral and central nervous system, which leads to an increased ability to perceive pain stimuli. Although there is evidence that plastic changes in the cortex contribute to this process, the underlying molecular mechanisms are unclear. Ko et al. (2018) show that activation of the anterior cingulate cortex (ACC) induced by peripheral nerve injury increases the turnover of neural cell adhesion molecule 1 (NCAM1), one of the molecules involved in nociception, our ability to detect painful stimuli. They further show that NCAM1 mediates spine reorganization and contributes to the behavioral sensitization patients experience.
11 | Field Trip to Vertex Pharmaceuticals | Progress in human health is one of the core missions of scientific research. Over many years biomedical research has generated successful therapies utilizing small molecules, proteins, and cells. More recently, researchers have explored directed gene-targeting as a new therapeutic modality. The discovery of the CRISPR/Cas9 system has revolutionized approaches to gene therapy and promises to vastly increase the power of personalized medicine. In addition, therapeutics for genetic disorders are becoming increasingly tractable as we begin to understand how to precisely target a gene or even a specific mutation of interest. Viral vectors and lipid-based cargo delivery systems to healthy cells are becoming increasingly more powerful and have greatly facilitated the delivery of gene therapies. Today we will visit Vertex Pharmaceuticals, a biotechnology/pharmaceutical company focused on discovering, developing, and producing innovative medicines so people with complicated diseases can lead a better life. We will learn about a novel approach to treating neuromuscular disorders and cystic fibrosis by delivering the CRISPR/Cas9 gene-editing technology to cells. Students will also have a chance to ask the researchers leading this effort about career paths and relevant graduate and postdoctoral skills. This experience will introduce students to cutting-edge technology used not only in the field of synapse dynamics but more generally across many disciplines in the field of molecular medicine.
12 | Fear and Trauma Deadline to choose paper for final presentation | The brain is the central regulator of stress and adaptation to stress, both critical for the perception of threats as well as for the appropriate behavioral and physiological responses to those threats. In humans, a single traumatic event or a period of prolonged intense stress can produce symptoms of post-traumatic stress disorder (PTSD). The neural structures important to PTSD belong to the limbic system, a set of brain regions localized near the thalamus and in the cortex, all important for emotional processing in both humans and animals. Because of the difficulty of studying PTSD in humans, rodent models of trauma and prolonged stress are being used to explore the neural mechanisms underlying PTSD. This week we focus on two different rodent models of trauma. In Lai et al. (2018), animals are exposed to an acute stressor (an electric shock), while in Colyn et al. (2019), animals are exposed to chronic social stress. These papers investigate the acute and long-term effects of stress on synaptic structures in sensory and limbic (i.e. emotional) brain regions. We will consider the benefits and limitations of different rodent models of trauma for understanding human PTSD.
13 | Nedivi Lab Visit: Technique Demonstrations | The laboratory of Dr. Elly Nedivi has made significant contributions to the field of synaptic plasticity in the visual system of rodents. They have developed methods for simultaneously imaging multiple synaptic proteins across entire dendritic arbors of neocortical neurons at diffraction-limited resolution in living mice. With this approach, it is possible to follow individual dendritic spines and inhibitory synapses as they are assembled and disassembled across the lifespan of an individual mouse. This visit will provide exposure to these cutting-edge in vivo imaging techniques and offer first-hand exposure to the methods behind some of the data we analyze during our weekly paper discussions. This week we will learn how the Nedivi group simultaneously monitored in vivo inhibitory and excitatory synapse dynamics across the entire dendritic arbors of pyramidal neurons using a 3-color system for 2-photon in vivo imaging. From Villa et al. (2016), we will learn how inhibitory synapses on dendritic shafts and spines differ in their distribution across the arbor and in their remodeling kinetics during normal and altered sensory experiences. Following our in-class discussion, we will visit the Nedivi laboratory to learn about how this technology is now being used to visualize both the pre- and postsynaptic side of a synapse simultaneously in the live mouse brain.
14 | Final Oral Presentations and Wrap-up Discussion | Students will give their oral presentations, including a brief question-and-answer session and discussion following each presentation. After the presentations, we will have a final discussion about what we learned throughout the course about synapse remodeling and about the benefits and limitations of different techniques and systems used to investigate synapse remodeling.

## Course Info

##### Instructors

- Dr. Dalila Ordonez
- Dr. Josiah Boivin

##### Departments

- Biology

##### As Taught In

Fall 2022

##### Level

Undergraduate

##### Topics

- Health and Medicine
  - Sensory-Neural Systems
- Science
  - Biology
    - Molecular Biology
    - Neurobiology
    - Neuroscience
  - Cognitive Science

##### Learning Resource Types

assignment Presentation Assignments
assignment Activity Assignments
assignment_turned_in Written Assignments with Examples
Readings

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