Glutamate and microglia activation as a driver of dendritic apoptosis: a core pathophysiological mechanism to understand schizophrenia

Abstract

Schizophrenia disorder remains an unsolved puzzle. However, the integration of recent findings from genetics, molecular biology, neuroimaging, animal models and translational clinical research offers evidence that the synaptic overpruning hypothesis of schizophrenia needs to be reassessed. During a critical period of neurodevelopment and owing to an imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, a regionally-located glutamate storm might occur, triggering excessive dendritic pruning with the activation of local dendritic apoptosis machinery. The apoptotic loss of dendritic spines would be aggravated by microglia activation through a recently described signaling system from complement abnormalities and proteins of the MHC, thus implicating the immune system in schizophrenia. Overpruning of dendritic spines coupled with aberrant synaptic plasticity, an essential function for learning and memory, would lead to brain misconnections and synaptic inefficiency underlying the primary negative symptoms and cognitive deficits of schizophrenia. This driving hypothesis has relevant therapeutic implications, including the importance of pharmacological interventions during the prodromal phase or the transition to psychosis, targeting apoptosis, microglia cells or the glutamate storm. Future research on apoptosis and brain integrity should combine brain imaging, CSF biomarkers, animal models and cell biology.

The Role of PDE11A4 in Social Isolation-Induced Changes in Intracellular Signaling and Neuroinflammation

“…Previously, we showed that deletion of PDE11A alters glutamatergic signaling in the hippocampus ( Pilarzyk et al, 2019 ; Kelly et al, 2010 ). Dysregulation of glutamatergic signaling is thought to contribute to the pathophysiology of schizophrenia, a neuropsychiatric disorder associated with deficits in social behaviors ( Parellada and Gassó, 2021 ). Social isolation has also been shown to decrease the release of glutamate in the hippocampus ( Almeida-Santos et al, 2019 ).…”

The role of microglia in neuropsychiatric disorders and suicide

“…However, a general blockade of microglial cells as a therapeutic intervention might have risky effects, since glutamate and activated microglial cells are involved in dendritic apoptosis. An excessive synaptic pruning during late adolescence and early adulthood might cause severe negative symptoms and a cognitive decline in patients with schizophrenia [205,206].…”

Subcortical volume reduction and cortical thinning 3 months after switching to clozapine in treatment resistant schizophrenia

“…Volumetric decreases during antipsychotic treatment may reflect tissue remodelling in response to physiological attempts to meet increased metabolic demands 90 , as clozapine and other antipsychotics can impair mitochondrial function [91][92][93][94] . However, it remains unknown whether the observed volumetric reductions and cortical thinning during clozapine treatment reflect excitotoxicity-induced apoptosis 54 , increased metabolic stress 90 , or neuroadaptive processes including compensatory pruning of neurons 95 , reduced microglial activation, and demyelination 36,72,73 or increases in subcortical white matter neuronal densities 74 . Future research could investigate these mechanisms further by combining structural MRI with indices of neuroinflammation, synaptic density 96 , peripheral mitochondrial activity, and central oxidative capacity 90 during treatment with clozapine.…”

“…There are several interacting biological mechanisms that may underlie the observed macrostructural changes in schizophrenia and during treatment with antipsychotics, including clozapine. Macrostructural deficits in schizophrenia are thought to principally reflect apoptotic loss of synapses and dendrites resulting from glutamate excitotoxicity 53,54 or neuroinflammation and microglial activation 14,55 , rather than neuronal loss [56][57][58] . Consistent with the expected effect of glutamate excitotoxicity, studies combining structural imaging with proton magnetic resonance spectroscopy ( 1 H-MRS) to measure regional glutamatergic metabolites find anterior cingulate cortex (ACC) glutamatergic metabolite levels are negatively associated with cortical thickness or volume 41,59 and caudate Glx (the sum of glutamate and its metabolite glutamine) is negatively associated with caudate volume in first episode psychosis 60 .…”