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genetic causes of autism and intellectual disability
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ADVICE AND INSIGHTS FROM UBC FACULTY ON REACHING OUT TO SUPERVISORS
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Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Palmitoylation is a reversible post-translational modification that facilitates vesicular transport and subcellular localization of modified proteins. This process is catalyzed by a family of palmitoyl acyltransferases known as zDHHC enzymes and mounting evidence suggests that these enzymes play key roles in the development and function of neuronal connections. Additionally, a number of zDHHCs have been associated with neurodevelopmental, neurological and neurodegenerative diseases. Loss-of-function variants in zDHHC15 and zDHHC9 are associated with intellectual disabilities; however, there is limited information on the function of these enzymes in the brain. This dissertation discusses work that demonstrates that zDHHC15 and zDHHC9 palmitoylation independently regulate dendritic arborization and are required for the formation and/or maintenance of excitatory (zDHHC15) and inhibitory (zDHHC9) synapses, thereby regulating the balance between excitation and inhibition. Loss of zDHHC15 function inhibits dendrite growth and decreases the palmitoylation and trafficking of PSD-95 into dendrites, leading to deficits in spine maturation. Loss of zDHHC9 function promotes dendritic retraction through aberrant palmitoylation of the small GTPase, Ras, and decreases the formation/maintenance of inhibitory synapses by decreasing the palmitoylation of the small GTPase, TC10. As well, knocking out zDHHC9 in mice results in decreased palmitoylation of Ras and TC10, and leads to elevated synaptic excitability and seizure-like activity. This work provides new insights into the function of zDHHC15 and zDHHC9 and provides a plausible mechanism for how loss-of-function mutations in these proteins may contribute to the etiology of intellectual disability
Synapses of the central nervous system are specialized points of cell-cell contact that transmit signals from one neuron to another in an efficient manner. A fundamental property of synapses is that they can be altered in response to activity, a process called “synaptic plasticity.” Synaptic activity can cause lasting increases in synaptic strength (long-term potentiation, or ‘LTP’), and decreases in synapse strength (long-term depression, or ‘LTD’).The cell adhesion molecules ‘cadherins’ and their intracellular binding partners β-catenin and δ-catenin are key mediators of synaptic plasticity. The disruption of the cadherin adhesion complex impairs LTP, and increased cadherin stability at synaptic membranes impairs LTD. The role of cadherins in synaptic plasticity has been well studied in the hippocampus, and cadherins have been shown to influence spatial learning and memory. However, little is known about the importance of cadherins in other brain regions, and in other forms of learning. In the first half of this dissertation, I examine the role of the cadherin adhesion complex in cocaine-mediated plasticity in the ventral tegmental area (VTA) of the mesocorticolimbic dopamine circuit. I demonstrate that cadherins play an important role in activity- and cocaine-mediated plasticity in the VTA. Furthermore I find that increasing cadherin localization at the synaptic membranes of VTA dopamine cells impairs AMPA receptor trafficking, synaptic plasticity, and cocaine-mediated behavioural conditioning.Previous work has also shown that the cadherin adhesion complex protein, δ-catenin, can be modified through the addition of the fatty acid, palmitate, to cysteine residues in a process called palmitoylation. δ-catenin palmitoylation results in increased cadherin-δ-catenin interactions and increases in synapse strength. The palmitoylation of δ-catenin is mediated by the palmitoyl acyltransferase, zDHHC5. Although zDHHC5 has been shown to play an important role in synaptic plasticity, its role in neuronal development has not been examined. In the second half of this dissertation, I examine the role of zDHHC5 in dendrite outgrowth and synapse formation, finding that the palmitoylation function and proper localization of zDHHC5 at the plasma membrane of postsynaptic spines are important for the stability of dendritic spines and the formation of excitatory synapses.
A fundamental property of synapses is their ability to change in response to activity, termed ‘synaptic plasticity’. Synaptic activity can cause long-lasting increases in the strength of synapses (long-term potentiation, or ‘LTP’), as well as decreases in synapse strength (long-term depression or ‘LTD’), both of which are believed to be important for learning and memory. The synaptic adhesion molecules ‘cadherins’ and their intracellular binding partner β-catenin have been identified as key mediators of plasticity at synapses. The cadherin adhesion complex is important for maintaining the strength and stability of synapses, and disruption of cadherin function has been shown to impair long-term potentiation (LTP). However, it remains unclear how increases in cadherin adhesion can affect synaptic function and cognition. This is important in light of studies showing that increases in β-catenin levels and mutations in cadherin adhesion complex proteins are associated with many different neurodegenerative diseases, as well as psychiatric disorders such as drug abuse, raising the possibility that aberrant increases in cadherin adhesion may contribute to cognitive impairments in these disorders. In this dissertation, I examine the effects of increases in cadherin adhesion on different forms of synaptic plasticity in the brain. I demonstrate that increases in β-catenin in the hippocampus can stabilize cadherin at the synaptic membrane and abolish long-term depression (LTD) at synapses, leading to significant impairments in spatial memory flexibility and reversal learning. I also demonstrate a role for cadherin in activity- and drug-induced plasticity in the ventral tegmental area (VTA), a region of the brain important for reward learning which is implicated in addiction, and show that cocaine-mediated conditioned place preference results in redistribution of cadherin and AMPA receptors to excitatory synapses onto dopaminergic neurons in the VTA. Together, these results demonstrate that the β-catenin/cadherin adhesion complex plays an important role in several forms of learning and memory, and that aberrant increases in synaptic adhesion can have a detrimental effect on synaptic plasticity and cognitive function.
Synapses of the Central Nervous System are specialized junctions of cell-cell contact that transmit signals from one neuron to another in a rapid and efficient manner. Synapses are highly plastic structures that can be continually modified in response to fluctuations in neuronal activity. Changes in the number, size, and protein composition of synapses have been observed following alterations in neuronal activity in vitro and following the learning of specific tasks in vivo. Thus, elucidating the molecular mechanisms underlying activity-mediated trafficking of proteins to and from synaptic compartments is essential for our understanding of brain function. Previous work has demonstrated a requirement for the cadherin-adhesion complex in activity-induced enhancements in synapse strength, however the molecular mechanisms that translate synaptic activation into enhanced cadherin-based adhesion and synapse strengthening remain unknown. This dissertation discusses work that unravels how synaptic activity coordinates the enhancement of cadherin surface stabilization, enlargement of dendritic spines, and increased surface insertion of AMPA receptors. This work demonstrates that increased synaptic activity enhances the palmitoylation of a brain-specific component of the cadherin-adhesion complex, δ-catenin, which in turn causes δ-catenin to traffic toward the synaptic membrane in spines where it associates with and stabilizes surface N-cadherin. This results in enhancements in synapse structure and efficacy, and is correlated with the acquisition of contextual fear memories. Furthermore, we show that palmitoylation of δ-catenin is mediated by the palmitoyl acyl-transferase DHHC5, and that DHHC5 drives activity-induced increases in surface AMPA receptor levels through the palmitoylation of δ-catenin. Finally, we demonstrate that the activity-induced palmitoylation of δ-catenin by DHHC5 is accomplished through the rapid trafficking of DHHC5 out of the synapse and into the dendritic shaft where it can associate with and palmitoylate δ-catenin, resulting in δ-catenin’s synaptic recruitment. This work provides new insights into the cellular and molecular mechanisms that underlie activity-induced synapse plasticity.
No abstract available.
Cell adhesion molecules (CAMs) have emerged as important players in synapse development; however, the precise roles of these proteins at newly formed contacts remain unknown. In this thesis, I begin by providing an overview of synaptic structure and development, as well as a review of our current understanding of how key CAMs and associated proteins fit into this framework.In the second chapter, I demonstrate that members of the postsynaptically localized neuroligin (NL) family of CAMs, including NL1, NL2 and NL3, can trigger the formation of excitatory and inhibitory presynaptic terminals, and that while NL1 is enriched at excitatory contacts, NL2 localizes primarily to inhibitory sites. Neuroligin-mediated enhancement of inhibitory synapse density is blocked by a fusion protein containing the extracellular domain of the presynaptic neuroligin binding partner, neurexin-1β. Furthermore, overexpression of postsynaptic density-95 (PSD-95), a postsynaptic binding partner of neuroligins, results in a shift of NL2 from inhibitory to excitatory synapses. These findings reveal that multiple neuroligins control the number of inhibitory and excitatory synapses, and that localization of NL2 can be altered by scaffolding proteins.In the third chapter, I examine the mechanisms by which NL2 and NL3 are recruited to inhibitory and excitatory synapses, respectively. To this end, I assessed the roles of PSD-95 and gephyrin, a postsynaptic scaffolding molecule localized exclusively to inhibitory synapses, in localizing NL2 and NL3. Knockdown of gephyrin results in a shift of NL2 from inhibitory to excitatory synaptic contacts, while knockdown of PSD-95 leads to a shift of NL2 and NL3 from excitatory to inhibitory contacts. Deletion of a discrete region within the C-terminus of NL2 reveals that the intracellular tail is required for the normal synaptic clustering of this protein. Together, these data suggest that intracellular mechanisms are involved in the synaptic targeting of different neuroligin family members.Overall, these results demonstrate an important role for neuroligins in the development of glutamatergic and GABAergic synapses, and indicate that postsynaptic scaffolding molecules modulate the targeting of neuroligins to distinct postsynaptic compartments. The final chapter of the thesis provides a general discussion relating these findings to other recent advancements in the field.
Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
The formation and remodelling of synaptic contacts require the precise distribution and trafficking of proteins to specialized compartments. This dynamic trafficking of synaptic proteins is partly controlled by palmitoylation, which is the most common form of post-translational lipid modification in the brain. Notably, several studies have shown that synaptic proteins can be differentially palmitoylated in response to stress and synaptic activity. However, it is unclear how changes in synaptic activity alters protein palmitoylation. To further understand the mechanism underlying activity-induced differential palmitoylation of proteins, primary rat hippocampal cultures were used to test whether increased synaptic activity impacts transcriptional regulation or post-translational modifications of palmitoylating (zDHHCs) and depalmitoylating (ABHD17) enzymes. There were no overall changes in the transcriptional profile of the 23 DHHC enzymes nor the thioesterase, ABHD17. Post-translational modifications were not observed for zDHHC8 following increased synaptic activity. In contrast, changes were identified in the dynamic phosphorylation and/or palmitoylation of zDHHC2, zDHHC5, zDHHC6 and zDHHC9 that impact the stability or enzymatic activity of the enzymes. These modifications are likely to be important for downstream palmitoylation of synaptic proteins and the modulation of synapse plasticity.
The formation and remodeling of specialized junctions between neurons, called synapses, requires precise distribution and trafficking of proteins to specialized compartments. Synapse plasticity refers to the continual changes in the strength and structure of these synaptic contacts that occur in response to neuronal activity. This is in large part mediated by post-translational modifications of synaptic proteins, including reversible protein palmitoylation, resulting in the strengthening and weakening of synaptic connections that underlies the cellular basis of learning and memory. To understand how the dynamic palmitoylation of neuronal proteins contributes to synaptic plasticity, we used an unbiased, proteomic approach to identify proteins that were differentially palmitoylated following a hippocampal-dependent fear conditioning learning paradigm in mice. In this study, we identified 121 hippocampal proteins, including several key synaptic proteins, whose palmitoylation status was altered 1 hour after contextual fear conditioning.A subset of the 121 differentially palmitoylated proteins was validated in vitro and the effects of dynamic palmitoylation on the function of a validated protein, lipid phosphate phosphatase-related protein 4 (LPPR4 – also referred to as plasticity-related gene 1, PRG-1), was investigated further. We demonstrate that PRG-1 palmitoylation is regulated by changes in neuronal activity associated with hippocampal learning as well as with chemical long-term potentiation (cLTP). We identified cysteine residues in PRG-1 that are palmitoylated and found that palmitoylation at these sites is important for dendritic spine formation. Furthermore, we demonstrate that increased palmitoylation of PRG-1 negatively regulates bioactive lipid uptake in dendritic spines and shafts and is important for activity-induced insertion of AMPA receptors into the postsynaptic membrane which is essential for synaptic strengthening. As palmitoylationivcan facilitate interactions between proteins and cellular membranes, we tested the hypothesis that neuronal activity modulates membrane surface levels of PRG-1 through palmitoylation. However, we discovered that activity-induced palmitoylation of PRG-1 had no effect on its surface expression and therefore likely functions through an alternative mechanism. These findings suggest that dynamic palmitoylation of PRG-1 contributes to hippocampal synapse plasticity by modulating bioactive lipid uptake, spine formation, and activity-induced AMPA receptor recruitment. Together, this study identifies dynamic palmitoylation networks which may be central to learning and memory.
Protein palmitoylation, the process by which palmitic acid is reversibly added to protein substrates, is the most common post-translational lipid modification in the brain. Palmitoylation is facilitated by a family of palmitoyl acyltransferases, called Zdhhc enzymes, and a number of mutations in genes encoding these enzymes are associated with neurological disorders. Loss-of- function variants in the human ZDHHC9 gene have been identified in patients diagnosed with X- linked intellectual disability (XLID). Multiple clinical studies have shown that the brains of patients with ZDHHC9 mutations have regional changes in white matter content, including reductions in overall white matter volume and alterations in the microstructure of white matter tracts, and in vivo research has demonstrated that Zdhhc9 mice exhibit similar reductions in corpus callosum volume. This dissertation discusses work showing that Zdhhc9 is highly expressed in the corpus callosum and oligodendrocytes, and that loss of Zdhhc9 in vivo may impact myelin formation. Zdhhc9 expression is nearly two-fold higher in the corpus callosum than in any other region of the mouse brain, and is consistently enriched in oligodendrocyte expression data from multiple, independent RNA-seq studies. In the brains of Zdhhc9 knockout mice, there are significant reductions in the overall protein levels of myelin/myelinating oligodendrocyte-associated markers, MBP, MOG, and PLP, and in the palmitoylation levels of MOG and PLP. We also observed trends suggesting altered distribution of myelin in the primary visual cortex (V1) of Zdhhc9 knockout mice. This work provides new perspectives into the role of Zdhhc9 in oligodendrocytes and provides evidence that palmitoylation contributes to the development of white matter.
Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder primarily characterized by stereotypic behaviors, deficits in social interaction and difficulties with communication. Extensive epidemiological studies suggest a major role for genetics in the etiology of ASD. To date, 600-1,200 human genes have putatively been linked to ASD, including SEMA5A and PTEN. A large number of these ASD-associated genes play a role in the formation, maintenance, elimination or stabilization of synapses, while others are involved in broader elements of neurodevelopment, such as dendrite arborization, dendritogenesis, and soma size. Consistent with neurological dysfunction in ASD are observations that individuals with ASD often have supernumerary synapses, disrupted excitatory/inhibitory balance, and patterns of hypo- and hyper-connectivity compared to the general population. Despite this, many of the neurological functions of ASD-associated genes or gene disruptions remain poorly elucidated.In this study, we examine the role of Sema5A in activity-mediated synapse elimination, notably hippocampal long-term potentiation (LTP) and long-term depression (LTD). We describe the enhanced trafficking of Sema5A to the surface membrane during LTD and the subsequent Sema5A-dependent elimination of excitatory synapses. Furthermore, we demonstrate that Sema5A selectively mediates excitatory—and not inhibitory—synapse elimination, suggesting a mechanism by which the dysregulation of Sema5A could disrupt excitatory/inhibitory balance. Secondly, we describe the role of PTEN in negatively regulating excitatory synapse density, total dendritic arbor length, and soma size. Moreover, we characterize alterations to the neurological functions of PTEN in mature hippocampal neurons following the introduction of ASD-associated single nucleotide variants (SNVs). We demonstrate that most of the ASD-associated PTEN SNVs tested are broadly loss of function, with two notable exceptions: P38H PTEN exhibits a single altered neurological function, while H123Q PTEN phenocopies wild type human PTEN across all measures, further stressing the importance of biological functionalization. Lastly, we establish a PTEN knockdown assay in which PTEN SNVs could be tested for synaptic, dendrite and somal phenotypes. Combined and integrated, the functionalization of ASD-associated genes and gene variants could permit greater accuracy in ASD diagnoses and prognoses, as well as the improved targeting of therapeutic interventions.
The semaphorins are a large protein family, highly conserved across diverse phyla. They are expressed throughout the body, with a diversity of functions including axon guidance, synapse development and plasticity, cell proliferation and migration, dendritic arborization, and neuronal polarization. Class 5 semaphorins, Sema5A and Sema5B, are highly similar transmembrane proteins, functioning in developmental axon guidance and synapse plasticity. Sema5A is genetically-linked to Autism Spectrum Disorder (ASD) and its expression is decreased in people with ASD. However, its function in synapse plasticity is poorly understood. Our study examines the role of Sema5A in synapse elimination and the regulation of class 5 semaphorins by neural activity, specifically long-term potentiation (LTP) and long-term depression (LTD). We demonstrate that Sema5A, like Sema5B mediates synapse elimination of hippocampal neurons. Furthermore, we show that the expression of both class 5 semaphorins is up-regulated by LTD and that LTD enhances the membrane localization of Sema5A. As LTD and Sema5A were independently found to mediate synapse elimination and as we determined that Sema5A is up-regulated by LTD, we tested the hypothesis that LTD-mediates synapse elimination through Sema5A up-regulation. However, we discovered that Sema5A is not required for LTD-mediated synapse elimination and therefore likely functions to eliminate synapses through a separate pathway.
Progranulin (PGRN) is a multi-functional, secreted growth factor expressed in a variety of tissues throughout the body. In the central nervous system (CNS), PGRN is expressed in microglia as well as in a number of neuronal populations and has been shown to promote neuronal survival, enhance neurite outgrowth and regulate inflammation and development. Mutations in the progranulin (GRN) gene have been identified as a major cause of autosomal dominant frontotemporal dementia (FTD) with tau-negative inclusions. The majority of GRN mutations result in the production of a null allele and reduced PGRN expression. However, the normal functions of PGRN in the CNS remain poorly understood. Our study examines the secretion characteristics of PGRN in neurons. To study the secretion of PGRN from axons and dendrites, we have fused a pH-sensitive optical reporter of exocytosis, superecliptic pHluorin, to PGRN (PGRN-SEP). We demonstrate that activity enhances the secretion of PGRN from axons and dendrites with different temporal profiles of secretion. We show, using calcium blockers and calcium-free media, that activity-mediated secretion of PGRN requires Ca²⁺ entry via voltage-gated calcium channels (VGCC). We postulate that activity-dependent secretion of PGRN may enhance the formation and maturation of synapses as treatment of hippocampal neurons with recombinant PGRN results in an increase in synapse density.
Cadherins and Neuroligins (NLs) are two of the most extensively studied cell adhesion molecules (CAMs) at synapses and have previously been shown to localize to synapses and exert a key role during their development. Despite this, their spatial and functional relationship with respect to one another has not been studied to date. In the present study, we examine the spatial and functional relationship of cadherin and NL isoforms at glutamatergic and GABAergic synapses in cultured hippocampal neurons. Analysis of the synaptic distribution of N-cadherin and NL1 and NL2 in hippocampal cultures, confirm previous studies demonstrating the enrichment of NL2 at GABAergic synapses and enrichment of NL1 and N-cadherin at glutamatergic synapses. We have also observed subsets of GABAergic synapses that express both N-cadherin and NL2 as well as glutamatergic synapses that only express either NL1 or N-cadherin. These groups of glutmatergic and GABAergic synapses may represent a specific subtype of synapse, or may reflect the differential localization of these adhesion molecules during synapse formation. Moreover, using a combination of overexpression and knockdown analysis we demonstrate that NL1 and N-cadherin promote the formation of synapses, in part, by a common pathway. Indeed, knocking down these proteins individually results in approximately 50% reduction in glutamatergic synapse density with a similar reduction upon combined knockdown. In addition, functional compensation assays demonstrate that NL1 expression can fully rescue synapse loss that is due to knockdown of N-cadherin expression. Furthermore, N-cadherin expression can partially rescue synapse loss that is due to knockdown of NL1 expression. Together this work demonstrates that these two cell adhesion proteins act in concert to regulate excitatory synapse formation. Specifically, we show that N-cadherin acts upstream of NL1 to promote synapse formation and that NL1 is a limiting factor in this pathway.
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