The nervous system comprises two classes of cells: neurons and glia. For a long time, neurons have been considered to be the sole basis for information integration, while glia have been thought to play a merely supportive role. However, this dogma is now being challenged. Recent studies show that signals can pass back and forth between neurons and glia. Rather than being a quiet bystander, glia likely participate in the active signal processing in the nervous system. While the projects summarized above focus on neurons in the brain, other projects in my lab examine the roles of glia. The most intriguing role is glial function at synapses. So far, much of our knowledge about the glia-synapse relationship has come from in vitro culture studies, with limited in vivo investigations mostly came from single time-point, fixed tissue examination. Given the complexity and variability of synaptic connections in the nervous system, the field is crying for longitudinal data of glia-synapse interaction in living animals. My lab approaches this question from two angles:
Role of astrocytes at CNS synapses: A major challenge to studying functions of cortical astrocytes (major glia in the brain) in vivo has been the paucity of molecular markers to facilitate genetic manipulation. For example, although the glial acidic fibrillary protein (GFAP) is widely regarded as an astrocytic marker, it is not expressed by most astrocytes in the healthy mature cortex. Recently, it has been suggested that some cortical astrocytes in the mature brain expresses the transcription factor, Gli1, in response to active Shh signaling. We therefore characterized a Gli1CreER mouse line in detail during the past two years and confirmed that Gli1+ cells represent a subset of cortical astrocytes in adult mice. Taking advantage of the inducible Cre/loxP strategy, we can now target this subset of cortical astrocytes for selective manipulation in vivo. We are currently exploring the roles of these subset astrocytes in synapse formation and stability, as well as their potential role in disease development.
Role of Schwann cells at the neuromuscular junction: Terminal Schwann cells (SCs) at neuromuscular junctions (NMJs) are the counterparts to astrocytes in the CNS. They are morphologically and functionally distinct from myelinating SCs, which are counterparts to oligodendricytes in the CNS. Compared to synapses in the CNS, the NMJ is much bigger in size and experimentally much more accessible. In this project, we investigate morphological changes of SCs at aging NMJs, as well as the possible cellular mechanisms underlying glial-synapse interactions for synapse remodeling. In my postdoctoral work, my colleagues and I generated transgenic mice that express different fluorescent proteins under glial- and neuronal-specific promoters (Zuo et al., 2004). In my lab, we imaged individual SCs in vivo, and captured their morphological dynamism with high temporal resolution. We found that SCs are mostly stable during adulthood. However, at the aging NMJs SCs become more dynamic, with progressive myelination occurring frequently at the axon entry site to the NMJs. This often results from a transition from terminal to myelinating SCs, and leads to loss of synaptic contact between motor axons and muscle fibers. In addition to changes from terminal to myelinating SCs, we also observed more cases of addition and removal of SCs at aged NMJs in chronic imaging. In order to investigate how individual terminal SC’s territory changes in association with the addition/removal of SCs, we sequentially dye-filled individual SCs with rodamine-dextran, and showed that adult SCs are arranged in a static tile pattern, while young SCs dynamically intermingle. Furthermore, in collaboration with Dr. Thomas Misgeld’s lab in Munich, we demonstrated that glial segregation is due to spatial competition, where glial-glial and axonal-glial contacts constrain the territory of single SCs. Part of these results has been published in Neuron Glia Biology (Zuo and Bishop, 2008) and The Journal of Cell Biology (Brill et al., 2011).
The projects summarized above will provide first-hand information on how glia modulate synaptic connections, such as synapse formation, elimination and plasticity. Since the synapse is believed to be the site of information exchange in the nervous system and is characterized by structural changes during learning and memory, understanding glial cells’ roles in structural plasticity of synapses should provide valuable knowledge on how information is transferred, integrated and stored in the nervous system. In addition, better understanding of glial involvement in aging and neurological diseases will likely lead to identification of therapeutic targets for neurological pathologies.
Zuo Y, Lubischer JL, Kang H, Tian L, Mikesh M, Marks A, Scofield VL, Maika S, Newman C, Krieg P and Thompson W (2004) Fluorescent proteins expressed in mouse transgenic lines mark subsets of glia, neurons, and immune cells for vital examination. J. Neurosci. 24(49):10999-11009. [PDF]
Zuo Y and Bishop D (2009) Glial imaging during synapse remodeling at the neuromuscular junction. Neuron Glia Biology 4(4):319-326. [PDF]
Brill MS, Lichtman JW, Thompson W, Zuo Y, Misgeld T. (2011) Spatial constraints dictate glial territories at murine neuromuscular junctions. J Cell Biol. 2011 Oct 17;195(2):293-305. [PDF]
Yu X, Wang G, Gilmore A, Yee AX, Li X, Xu T, Smith SJ, Chen L, Zuo Y (2013) Accelerated experience-dependent pruning of cortical synapses in ephrin-A2 knockout mice. Neuron 80(1): 64-71 [PDF]
Hodges JL, Yu X, Gilmore A, Li X, Perna JF, Tjia M, Chen C-C, Bennett H, Lu J and Zuo Y (2017) Astrocytic contributions to synaptic and learning abnormalities in a mouse model of Fragile X Syndrome. Bio. Psych. 82(2):139-149 [PDF]