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 2ϩ ] 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 2ϩ ] 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 2ϩ 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.

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

“…Recent in vitro work in our laboratory showed that the contribution and composition of the NMDA receptors are altered following stretch injury (Patel et al, 2014b), and we asked if a similar phenomenon occurred after primary blast loading. We therefore tested if the relative contribution of the NMDA receptors to the field potential was affected after primary blast loading (Fig.…”

Glutamate and GABA Imbalance Following Traumatic Brain Injury

“…Activation of NR2B results in prolonged calcium influx that appears to be more specifically taken up by mitochondria, leading to subsequent mitochondrial dysfunction and increased activity of caspases, all of which promote cell damage and demise [28–30]. Finally, NR2B containing neurons are more susceptible to mechanical injury versus NR2A neurons and a greater proportion of NR2B neurons leads to impaired neuronal connectivity and plasticity [31,32]. Shifts in these NMDAR subunits have important ontogenic and functional consequences.…”

Interference of neuronal activity‐mediated gene expression through serum response factor deletion enhances mortality and hyperactivity after traumatic brain injury

“…7 Particularly within the first hours after TBI, an increased neuronal excitability and reduced GABAergic inhibitory transmission were reported. [8][9][10][11][12] Such early neuronal hyperexcitability involves NMDA receptor subunit upregulation 7 and a function of, for example, GluN2B as injury mechanoreceptors. 9 Taken together, previous reports describe enhanced neuronal activity at early stages after TBI.…”