Michael Fox

Fox laboratory: Center for Neurobiology Research

Synapses are specialized sites that allow information to be passed between neurons. Their importance is highlighted by the fact that even minor synaptic abnormalities, caused by disease or neurotrauma, result in devastating neurological conditions. Understanding how CNS synapses are formed is therefore essential to our understanding of neurological disorders. The Fox Laboratory is interested in understanding the cellular and molecular mechanisms that drive the initial formation of synapses, as well as their maturation and long-term maintenance.

One area of interest in the Fox laboratory is to understand the mechanisms that allow growing axons to selectively target appropriate regions (and neurons within those regions) to form lasting synaptic connections with – a process called synaptic targeting. For these studies, we focus our attention on the developing visual system and ask how synapses are formed between retinal ganglion cells (RGCs), the output neurons of the retina, and target neurons within the brain. Spurred on by Roger Sperry’s postulation of the chemoaffinity hypothesis (which postulated that regionalized chemical cues direct topographic mapping of RGC axons within the brain), many groups have searched for and identified chemical/molecular cues necessary for the correct exiting of retinal ganglion cell axons from the retina, the correct crossing of RGC axons at the optic chiasm, the repulsion of RGC axons from non-retinal targets, and the topographic mapping of RGC axons within the lateral geniculate nucleus (LGN) and superior colliculus (SC). Despite these monumental advances, it still remains unclear how different subtypes of RGCs – of which there are more than 40 – target functionally distinct nuclei within the brain.

A second are of interest in the Fox lab is to understand the trans-synaptic signals exchanged between pre- and postsynaptic partners (and glial cells!) that are required for the proper assembly of chemical synapses. Such signals include cell adhesion molecules as well as secreted factors, such as growth factors, morphogens, and extracellular matrix proteins. We investigate the role of such factors in both the developing subcortical visual system, as well as in non-visual areas of the cerebral cortex and hippocampus. For example, in one long standing project in the lab we have identified novel roles for a unique family of extracellular matrix proteins in synaptic development in the brain. This family of extracellular matrix molecules, termed unconventional (or non-fibrillar) collagens, had been found to direct synaptic differentiation and maturation at the neuromuscular junction (NMJ) — a large peripheral synapse between motoneurons and muscle fibers. Specifically, controlled proteolysis of several collagen molecules at the NMJ generates soluble peptides that exhibit unique bioactivities compared to the full-length molecule from which they are derived. These proteolytically released fragments of collagen molecules are termed ‘matricryptins’ and at the NMJ collagen-derived matricryptins have been shown to direct pre- and postsynaptic assembly and maturation. Based upon bio-activities of these matricryptin-releasing collagens at the NMJ and their expression in the brain, we have explored their synaptic roles at central synapses. Why is this important? Besides advancing our basic knowledge of brain development, these families of ECM molecules are highly mutated in humans and many of these mutations cause unexplained neurological deficits (including schizophrenia, autism spectrum disorders, and epilepsy).

Finally, the Fox lab’s newest direction involves understanding how infectious agents alter the maintenance of neural circuits in the mammalian brain. We are particularly interested in Toxoplasma gondii, an obligate, intracellular parasite that can resides in the brain and skeletal muscle of most warm-blooded animals. Approximately 25% of the US population is infected with this parasite and once infected you remain infected for life. Active infections with Toxoplasma gondii in infants, HIV/AIDS patients, or those with weakened immune systems can lead to toxoplasmosis. However, a number of more recent studies have revealed chronic infections of this parasite can lead to altered behaviors and have been associated with various neurological diseases. In fact, infection with Toxoplasma gondii appears to be a higher risk factor for developing schizophrenia than any single gene mutation identified to date. With this in mind, we are actively investigating how infection with Toxoplasma gondii alters neural circuits that have been previously linked to schizophrenia.

Learn more about Dr. Fox research Lab

Selected Publications:  

• Sabbagh, U., Govindaiah, G., Somaiya, R. D., Ha, R. V., Wei, J. C., Guido, W., & Fox, M. A. (2020). “Diverse GABAergic neurons organize into subtype-specific sublaminae in the ventral lateral geniculate nucleus.” JNeurochem, in press 2020.
• Carrillo, G., Ballard, V., Glausen, T., Boone, Z., Teamer, J., Hinkson, C., Wohlfert, E., Blader, I. Fox, M.A. “Toxoplasma infection induces microglia‐neuron contact and the loss of perisomatic inhibitory synapses.” Glia.  2020; 1– 19.
• Su, J., Charalambakis, N.E., Sabbagh, U, Somaiya, R., Monavarfeshani, A., Guido, W*, Fox, M.A.* “Retinal Inputs Signal Astrocytes to Recruit Interneurons into Visual Thalamus.” PNAS. Jan 2020; DOI:10.1073/pnas.1913053117 (* co-corresponding authors).
• Monavarfeshani, A., Stanton, G., Van Name, J., Su, K., Mills, W.A., Swilling, K., Kerr, A., Su, J., Fox, M.A. “LRRTM1 underlies synaptic convergence in visual thalamus.” Elife. 2018 Feb 9;7.
• Su, J., Chen, J., Carrillo, G., Lippold, K., Monavarfeshani, A., Jenkins, R., Fox, M.A. “Collagen-Derived Matricryptins Promote Inhibitory Nerve Terminal Formation in the Developing Neocortex.” J Cell Biol. 2016 Mar 14;212(6):721-36.
• Hammer, S., Lemon, T., Monavarfeshani, A., Su, J., Fox, M.A. “Multiple retinal axons converge onto relay cells in the adult mouse thalamus.” Cell Rep. 2015 Sept 8;12(10): 1575-83.

For more Dr. Fox publications please check PubMed

NEUR 4044: Brain under attack (Neuroscience Senior Seminar)