title: Single-neuron NMDA receptor phenotype influences neuronal rewiring and reintegration following traumatic injury.
abstract: Alterations in the activity of neural circuits are a common consequence of traumatic brain injury (TBI), but the relationship between single-neuron properties and the aggregate network behavior is not well understood. We recently reported that the GluN2B-containing NMDA receptors (NMDARs) are key in mediating mechanical forces during TBI, and that TBI produces a complex change in the functional connectivity of neuronal networks. Here, we evaluated whether cell-to-cell heterogeneity in the connectivity and aggregate contribution of GluN2B receptors to [Ca(2+)]i before injury influenced the functional rewiring, spontaneous activity, and network plasticity following injury using primary rat cortical dissociated neurons. We found that the functional connectivity of a neuron to its neighbors, combined with the relative influx of calcium through distinct NMDAR subtypes, together contributed to the individual neuronal response to trauma. Specifically, individual neurons whose [Ca(2+)]i oscillations were largely due to GluN2B NMDAR activation lost many of their functional targets 1 h following injury. In comparison, neurons with large GluN2A contribution or neurons with high functional connectivity both independently protected against injury-induced loss in connectivity. Mechanistically, we found that traumatic injury resulted in increased uncorrelated network activity, an effect linked to reduction of the voltage-sensitive Mg(2+) block of GluN2B-containing NMDARs. This uncorrelated activation of GluN2B subtypes after injury significantly limited the potential for network remodeling in response to a plasticity stimulus. Together, our data suggest that two single-cell characteristics, the aggregate contribution of NMDAR subtypes and the number of functional connections, influence network structure following traumatic injury.
authors.affiliation: Departments of Bioengineering and Neurosurgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Tapan P
authors.initials: TP
authors.lastname: Patel
authors.forename: Scott C
authors.initials: SC
authors.lastname: Ventre
authors.forename: Donna
authors.initials: D
authors.lastname: Geddes-Klein
authors.forename: Pallab K
authors.initials: PK
authors.lastname: Singh
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology; D009415:Nerve Net / Q000378:metabolism* / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate
keywords: GluN2B; functional connectivity; mechanical injury; network activity; synchrony