Reduced d-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia

Park, Deborah K.; Petshow, Samuel; Anisimova, Margarita; Barragan, Eden V.; Gray, John A.; Stein, Ivar S.; Zito, Karen

doi:10.1016/j.nbd.2022.105772

Cited by 17 publications

(19 citation statements)

References 93 publications

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“…This assumption is supported by experiments as it has been shown that GC spine dynamics depend on GC activity [27,28,29]. Moreover, the formation and removal of consolidated synapses appear to be separate processes that depend on the calcium concentration at the synapse [26,79,80]. Therefore we express the rate R + i,j…”

Section: Synaptic Plasticitymentioning

confidence: 78%

“…To characterize learning-induced subnetworks within the OB, we performed hierarchical clustering using an agglomerative approach with Ward linkage on the columns of the connectivity matrix between MCs and GCs [Pedregosa et al, 2011]. We then sought to identify the number of clusters present in the data using the resulting distances between groups of points returned by the algorithm.…”

Section: Clustering Analysismentioning

confidence: 99%

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Adult Neurogenesis Reconciles Flexibility and Stability of Olfactory Perceptual Memory

Sakelaris,

Riecke

2024

Preprint

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The abilities to learn and store memories are inherently at odds with each other: the brain must be flexible enough to quickly store new information, but stable enough to avoid overwriting old memories. We show that adult neurogenesis can overcome this flexibility-stability dilemma. We develop a computational model for adult neurogenesis and structural spine dynamics in the olfactory bulb that captures many experimental observations and show that the transient properties of adult-born neurons confer multiple contributions to addressing this problem. First, the enhanced plasticity of young neurons allows them to flexibly encode new memories; as the neurons age, these memories stabilize, while remaining in the same neural ensemble. Second, the young new neurons' enhanced excitability and susceptibility to apoptosis maintain the flexibility of the memory. Finally, the period of sensory-dependent dendritic elaboration establishes an additional substrate of memory that facilitates rapid relearning. The model makes experimentally testable predictions and identifies a new functional role of adult neurogenesis in olfaction: memory consolidation.

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Section: Synaptic Plasticitymentioning

confidence: 78%

Section: Clustering Analysismentioning

confidence: 99%

Adult Neurogenesis Reconciles Flexibility and Stability of Olfactory Perceptual Memory

Sakelaris,

Riecke

2024

Preprint

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“…We hypothesize that the diminished number of synapses in the surviving neurons may increase NMDAR signaling strength such that there is greater synaptic activity in the damaged neurons leading to more secretion of HMGB1, initiating a self-reinforcing cycle as HMGB1 potentiates NMDAR signaling 10,13 . Interestingly, increased NMDAR signaling in neurons with fewer synapses has been described in a mouse model of schizophrenia 35 . In our model, increased extracellular HMGB1 induces the secretion of proinflammatory cytokines, type I IFN, and C1q.…”

Section: Discussionmentioning

confidence: 99%

Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling

Carroll

Mizrachi

Simmons

et al. 2023

Preprint

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Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is initiated when anti-DNA, anti-N-methyl D-aspartate receptor (NMDAR) cross-reactive antibodies, which are present in 30% of SLE patients, penetrate the hippocampus. This leads to immediate, self-limited excitotoxic death of CA1 pyramidal neurons followed by a significant loss of dendritic arborization in the remaining CA1 neurons and impaired spatial memory. Both microglia and C1q are required for dendritic loss. Here we show that this pattern of hippocampal injury creates a maladaptive equilibrium that is sustained for at least one year. It requires HMGB1 secretion by neurons to bind RAGE, a receptor for HMGB1 expressed on microglia, and leads to decreased expression of microglial LAIR-1, an inhibitory receptor for C1q. The angiotensin converting enzyme (ACE) inhibitor captopril, which can restore a healthy equilibrium, microglial quiescence, and intact spatial memory, leads to upregulation of LAIR-1. This paradigm highlights HMGB1:RAGE and C1q:LAIR-1 interactions as pivotal pathways in the microglial-neuronal interplay that defines a physiologic versus a maladaptive equilibrium.

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“…We hypothesize that the diminished number of synapses in the surviving neurons may increase NMDAR signaling strength such that there is greater synaptic activity in the damaged neurons leading to more secretion of HMGB1, initiating a selfreinforcing cycle as HMGB1 potentiates NMDAR signaling 1,13 . Interestingly, increased NMDAR signaling in neurons with fewer synapses has been described in a mouse model of schizophrenia 35 . In our model, increased extracellular HMGB1 induces the secretion of proinflammatory cytokines, type I IFN, and C1q.…”

Section: Discussionmentioning

confidence: 99%

Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling

Diamond

2023

Preprint

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Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is initiated when anti-DNA, anti-N-methyl D-aspartate receptor (NMDAR) cross- reactive antibodies, which are present in 30% of SLE patients, penetrate the hippocampus1. This leads to immediate, self-limited excitotoxic death of CA1 pyramidal neurons followed by a significant loss of dendritic arborization in the remaining CA1 neurons and impaired spatial memory. Both microglia and C1q are required for dendritic loss. Here we show that this pattern of hippocampal injury creates a maladaptive equilibrium that is sustained for at least one year. It requires HMGB1 secretion by neurons to bind RAGE, a receptor for HMGB1 expressed on microglia, and leads to decreased expression of microglial LAIR-1, an inhibitory receptor for C1q. The angiotensin converting enzyme (ACE) inhibitor captopril, which can restore a healthy equilibrium, microglial quiescence, and intact spatial memory, leads to upregulation of LAIR-1. This paradigm highlights HMGB1:RAGE and C1q:LAIR-1 interactions as pivotal pathways in the microglial–neuronal interplay that defines a physiologic versus a maladaptive equilibrium.

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Reduced d-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia

Cited by 17 publications

References 93 publications

Adult Neurogenesis Reconciles Flexibility and Stability of Olfactory Perceptual Memory

Adult Neurogenesis Reconciles Flexibility and Stability of Olfactory Perceptual Memory

Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling

Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling

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