Electrophysiological Changes in Cortical-Striatal Synaptic Function in Mice with Ephrin-A5 Gene Deletions

Mark Gabriel

Mentor: Dr. Lawrence Kromer, Department of Neuroscience, Georgetown University.

Date/Time: June 26, 2020 at 3pm

Abstract: Understandings how neural connections form and are disrupted is important in determining the biological basis for developmental brain behavioral disorders and changes in brain functions that occur due to trauma or neurodegeneration. One class of cell-to-cell signaling proteins located on the surface of neurons, termed Eph receptors and their intercellular binding partners, ephrins, have been identified as being involved in the formation and organization of neural connections. Since there are fewer ephrins than Eph receptors, there is a hierarchical order in binding preference which results in competition in binding preference based on both binding affinity and contraction of these molecules on the surface on neurons and their processes.  My project in the Kromer lab focused on analyzing electrophysiological data from mice which lack a specific ephrin, ephrin-A5.  Experimental studies in mice with deletions of ephrin-A5 (5KO) demonstrate that this molecule is important for the proper formation of multiple brain connections.  Moreover, mice with deletions of this molecule develop unique subtypes of behavioral abnormalities. One important brain region that is disrupted in these mice is the striatum, which is an important brain center that is affected in disorders like ADHD, OCD, Autism, and Tourette’s.  Although anatomical changes in the brain and resulting behavioral dysfunctions in ephrin-A5 KO mice have been studied, the electrophysiological changes that occur in neuron-neuron communication are not clearly known.  Thus, my study focused on the analysis of electrophysiological data that measured changes in excitatory signaling at cortical-striatal synapses. Both mice with a single mutation of ephrin-A5 and a control group were analyzed. 

The electrophysiological changes in synaptic transmission were analyzed based on the different expression of a glutamate receptor, specifically the AMPA receptors in the dorsal medial and dorsal lateral striatum.  AMPA receptors have been shown to be one of the amino receptors that are correlated with Eph receptor prevalence.  Using Clampfit as the primary analysis tool, the differences between wild-type and ephrin-A5 KO mice was categorized using their capability to conduct a neural stimulus as well as their active membrane properties.  The differences in the electrophysiological properties on cortical-striatal synapses between the control and 5KO mice provides insight into the electrophysiological benefit of ephrins with regards to building neural pathways. These data, in conjunction with behavioral and histological data, show the importance of ephrins in the proper development and function of synaptic circuits within the striatum that could provide insight into therapeutic interventions for improving synaptic functions that are disrupted in developmental neurological disorders.