N-Methyl D-Aspartate glutamate Receptors (NMDAR) mediate excitatory synaptic transmission in the CNS and are critically involved in neuromodulation. Over the past fifty years, NMDAR have been found to play a central role in synaptic plasticity and experience-dependent adaptation, which are critical for cognitive functions, learning and memory. Impairments in NMDAR signalling have been associated with neurodegenerative processes including Alzheimer, Huntington, and Parkinson’s disease; psychiatric disorders such as schizophrenia, bipolar disorder, and depression; and, NDMAR impaired function was related to epilepsy, autism, and-or intellectual disability. Consequently, NMDAR research has attracted growing attention, focused on understanding how their properties shape physiological brain functions. Also, many efforts were aimed to find a causal link between the cellular and molecular changes leading to NMDAR impairments and the symptomatology of neurological and psychiatric disorders. Besides the characterization of their structural features and subunit-specific ion channel properties, recent advances have revealed that NMDAR display dynamic intracellular and surface trafficking that modifies synaptic organization and interactions into the postsynaptic density. Furthermore, it was shown that NMDAR exhibits distinct cellular and subcellular localization, and mediate non-ionotropic signalling. Together, these properties contribute to NMDAR physiological and pathological actions.
NMDAR are central actors of synaptic plasticity processes and cognitive functions. These cationic channels result from the assembly of two mandatory GluN1 subunits with two regulatory GluN2 (A-D) or GluN3 (A, B) subunits, leading to multiple combinations shaping receptor properties. NMDAR subunits expression are tightly regulated in time and space and evolve as a function of brain development and experience-dependent adaptations (e.g., memory formation and consolidation). NMDAR are closed at resting membrane potential and open only upon a combination of coincident pre-and post-synaptic events (presynaptic glutamate release, co-agonist release, postsynaptic depolarization), eventually allowing calcium influx and subsequent intracellular signalling leading to the addition or retraction of post-synaptic glutamate receptors. Any alteration to these channel gating and composition features is generally associated with severe brain conditions. Besides, accumulating evidence suggests that NMDAR-mediated signalling and plasticity can also proceed from ion flux-independent contributions; and, that aberrant synaptic anchoring, organization, or metabotropic signalling can also lead to NMDAR hypo- or hyperfunction in the context of brain disorders. In this Research Topic, we wish to provide a broad view of the latest advances in our understanding of how molecular architecture, gating, surface expression and trafficking, synaptic organization and interactions, ionotropic and non-ionotropic signalling of NMDAR; contribute to their function. We also wish to highlight how these parameters evolve both in a physiological context (e.g., development, plasticity) and following pathological alterations.
The aim of this Research Topic is to compile recent discoveries in NMDAR physiology and pathology, from a structural to a functional point of view. Topics of interest include but are not limited to:
• NMDAR molecular architecture, gating, expression, and organization
• NMDAR roles in synaptic physiology, learning and memory
• How pathological alterations to these NMDAR features contribute to the aetiology of brain diseases
• How NMDAR receptors can be targeted for therapeutic intervention
N-Methyl D-Aspartate glutamate Receptors (NMDAR) mediate excitatory synaptic transmission in the CNS and are critically involved in neuromodulation. Over the past fifty years, NMDAR have been found to play a central role in synaptic plasticity and experience-dependent adaptation, which are critical for cognitive functions, learning and memory. Impairments in NMDAR signalling have been associated with neurodegenerative processes including Alzheimer, Huntington, and Parkinson’s disease; psychiatric disorders such as schizophrenia, bipolar disorder, and depression; and, NDMAR impaired function was related to epilepsy, autism, and-or intellectual disability. Consequently, NMDAR research has attracted growing attention, focused on understanding how their properties shape physiological brain functions. Also, many efforts were aimed to find a causal link between the cellular and molecular changes leading to NMDAR impairments and the symptomatology of neurological and psychiatric disorders. Besides the characterization of their structural features and subunit-specific ion channel properties, recent advances have revealed that NMDAR display dynamic intracellular and surface trafficking that modifies synaptic organization and interactions into the postsynaptic density. Furthermore, it was shown that NMDAR exhibits distinct cellular and subcellular localization, and mediate non-ionotropic signalling. Together, these properties contribute to NMDAR physiological and pathological actions.
NMDAR are central actors of synaptic plasticity processes and cognitive functions. These cationic channels result from the assembly of two mandatory GluN1 subunits with two regulatory GluN2 (A-D) or GluN3 (A, B) subunits, leading to multiple combinations shaping receptor properties. NMDAR subunits expression are tightly regulated in time and space and evolve as a function of brain development and experience-dependent adaptations (e.g., memory formation and consolidation). NMDAR are closed at resting membrane potential and open only upon a combination of coincident pre-and post-synaptic events (presynaptic glutamate release, co-agonist release, postsynaptic depolarization), eventually allowing calcium influx and subsequent intracellular signalling leading to the addition or retraction of post-synaptic glutamate receptors. Any alteration to these channel gating and composition features is generally associated with severe brain conditions. Besides, accumulating evidence suggests that NMDAR-mediated signalling and plasticity can also proceed from ion flux-independent contributions; and, that aberrant synaptic anchoring, organization, or metabotropic signalling can also lead to NMDAR hypo- or hyperfunction in the context of brain disorders. In this Research Topic, we wish to provide a broad view of the latest advances in our understanding of how molecular architecture, gating, surface expression and trafficking, synaptic organization and interactions, ionotropic and non-ionotropic signalling of NMDAR; contribute to their function. We also wish to highlight how these parameters evolve both in a physiological context (e.g., development, plasticity) and following pathological alterations.
The aim of this Research Topic is to compile recent discoveries in NMDAR physiology and pathology, from a structural to a functional point of view. Topics of interest include but are not limited to:
• NMDAR molecular architecture, gating, expression, and organization
• NMDAR roles in synaptic physiology, learning and memory
• How pathological alterations to these NMDAR features contribute to the aetiology of brain diseases
• How NMDAR receptors can be targeted for therapeutic intervention
