- OverviewOur laboratory investigates the development and disorders of synapses - the specialized connections that allow communication between neurons and circuits - groups of neurons that function together.
Synapses are not static structures - but dynamically alter in number, function, shape and complexity during development and throughout adult life. The most remarkable capabilities of the brain such as learning and memory storage are thought to be possible through this plastic ability of synapses to change and respond to experience. Many synapses have exquisitely specialized roles - for example neuromuscular junction synapses between motor neurons and muscles are adapted to amplify small neuronal impulses into large muscle contractions. Synapses allow communication between groups of interconnected neurons which form circuits. Circuits are critical for animal behavior. For example, motor circuits process input from sensory neurons and the brain before sending output to motor neurons. A molecular understanding of how synapses and circuits develop, specialize and modify is a key step to illuminating the workings of the human brain. It is thought that many human neurological diseases like autism and schizophrenia as well as neuropathies such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and Alzheimer’s disease are caused by or induce defects in synaptic or circuit function and connectivity.
Live imaging of Drosophila neuromuscular junction synapse growth
The goal of our lab is to identify molecular signaling pathways that regulate synapse and circuit development and growth, decipher how neuronal activity modulates these processes and determine how disease disrupts synapse and neural network function. To address these questions, we study the synapses and circuitry of the fruit fly Drosophila melanogaster as a model system. Drosophila shares not only extensive genetic conservation to humans but also has many of the same morphological, physiological and behavioral complexities. Members of the lab combine their expertise in genetics, imaging, electrophysiology, molecular biology and biochemistry to collaborate on a number of projects arising from our screens for mutants that disrupt synapse development and from our models of human neurological disease.
- DevelopmentAbdominal hemisegments of Drosophila larvae have 30 muscle fibers which are stereotypically innervated by 36 motoneurons, each of which is uniquely identifiable allowing single cell experimental resolution. Drosophila larva grow at an extraordinary rate in the five days between embryo hatching and pupation increasing in body size by over 1000-fold. During this period, muscle surface areas undergo a 100–fold expansion and this increase in muscle size is accompanied by a concomitant increase in the size, complexity and neurotransmitter output of neuromuscular junction (NMJ) synapses. This dynamic morphological growth, coupled with the ability to carry out electrophysiological and ultrastructural studies makes the Drosophila NMJ an ideal synapse to study plastic changes during development. Furthermore, altering motor activity can also influence the growth and function of these synapses allowing experience dependent aspects of plasticity to be studied.
We have utilized transgenic fluorescent protein synaptic markers in a large forward genetic screen for novel mutants that perturb synaptic assembly, growth, structure and stability. Characterization of these mutants has revealed that the formation, growth and plasticity of synapses can be genetically dissected into discrete molecular and cellular events that integrate to ensure synaptic structural architecture is matched to requirements necessary for efficient neurotransmission.
Recent publications this topic - Beck et al. 2012, Choi et al. 2014
- CircuitsAnimals behaviors, including locomotion, depend upon the coordinated activity of neuronal networks. Disruption of individual components of neural circuits by injury or disease can produce a cascade of deleterious secondary effects upon other networked neurons. Chronic dysfunction of neuronal circuits has been hypothesized to lead to degeneration of neurons within the network, both exacerbating the damage and masking the primary cause of the disorder.
We have discovered surprising links between sensory-motor circuit function in Drosophila and the motor system disease Spinal Muscular Atrophy. Our results also suggest that aspects of motor circuit neural networks and regulatory genes may be conserved between Drosophila and mammals. We are endeavoring to expand on these findings to illuminate the identity and connectivity of motor circuit neurons in Drosophila.
See also drosophilabrain.org
Recent publications this topic - Imlach et al. (2012).
- DiseaseHistorically, invertebrate genetic models such as Drosophila have provided insights into human physiology and disease through basic research into fundamental biological mechanisms. However, in the post-genomic era, realization of the extraordinary degree of genetic conservation between humans and invertebrates has prompted the development of Drosophila models of human disease genes in order to conscript the sophisticated genetic and cellular tools available in this system.
Defective locomotion in an ALS motor neuron disease model
We have developed and continue to investigate Drosophila models of the juvenile motor system disease Spinal Muscular Atrophy, the adult motor neuron disease Amyotrophic Lateral Sclerosis and the brain neurodegenerative Alzheimer's disease. Together with our collaborators with are also involved in determining the molecular function of genes implicated in substance abuse and Parkinson's disease. We hope the molecular pathways and interacting genes discovered in Drosophila can serve as the basis for new drug or therapeutic targets to treat these human neurological disorders.
Recent publications this topic - Wang et al. 2011; Imlach et al. (2012) ; Lotti, Imlach et al. (2012)
- TechnologyDrosophila neuroscience has benefited from increasingly sophisticated genetic tools and methods that have lead to many important neurobiology discoveries.
For our own studies, we have constructed improved transgenesis tools. We continue to develop improved methods to image and manipulate synapses and circuits.
See also drosophilabrain.org
Recent publications on this topic - Wang et al. 2012.