Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations

Abstract

Activation of extrasynaptic N-methyl-d-aspartate (NMDA) receptors causes neurodegeneration and cell death. The disease mechanism involves a pathological triad consisting of mitochondrial dysfunction, loss of integrity of neuronal structures and connectivity, and disruption of excitation-transcription coupling caused by CREB (cyclic adenosine monophosphate-responsive element-binding protein) shut-off and nuclear accumulation of class IIa histone deacetylases. Interdependency within the triad fuels an accelerating disease progression that culminates in failure of mitochondrial energy production and cell loss. Both acute and slowly progressive neurodegenerative conditions, including stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease, share increased death signaling by extrasynaptic NMDA receptors caused by elevated extracellular glutamate concentrations or relocalization of NMDA receptors to extrasynaptic sites. Six areas of therapeutic objectives are defined, based on which a broadly applicable combination therapy is proposed to combat the pathological triad of extrasynaptic NMDA receptor signaling that is common to many neurodegenerative diseases.

Figure 1.

The pathological triad of extrasynaptic NMDA receptor signaling as a common converging point in neurodegenerative conditions. The pathological triad leads to impairments of cognitive functions and culminates in bioenergetics failure and neuronal cell death.

Figure 2.

Schematic illustration of the antagonism by extrasynaptic NMDA receptors of both local signaling and synapse-to-nucleus signaling activated by synaptic NMDA receptors. Not depicted, for simplicity, is the contribution of back-propagating action potential firing and opening of L-type voltage-gated calcium channels to activity-driven, synaptic NMDA receptor–dependent gene expression (Bading, 2013). Synapse-to-nucleus signaling is mediated by a propagating calcium signal (Bading, 2013) but in addition can involve protein-based communication pathways including the ERK-MAPK cascade, Jacob, and TORC1/2 (Hagenston and Bading, 2011; Panayotis et al., 2015). NMDA receptor–interacting protein (NIP) indicates a putative extrasynaptic NMDA receptor–interacting protein that may be part of the death-signaling complex. Local signaling and plasticity refers in particular to dendritic mRNA translation, AMPA receptor trafficking, and control of synaptic efficacy (Steward and Schuman, 2001; Kelleher et al., 2004; Kim et al., 2005; Costa-Mattioli et al., 2009). The six areas of therapeutic objectives described in this paper are indicated as A1–A6.