Converging synaptic and network dysfunctions in distinct autoimmune encephalitis.

Psychiatric and neurological symptoms, as well as cognitive deficits, represent a prominent phenotype associated with variable forms of autoimmune encephalitis, regardless of the neurotransmitter receptor targeted by autoantibodies. The mechanistic underpinnings of these shared major neuropsychiatric symptoms remain however unclear. Here, we investigate the impacts of patient-derived monoclonal autoantibodies against the glutamatergic NMDAR (NMDAR mAb) and inhibitory GABAaR (GABAaR mAb) signalling in the hippocampal network. Unexpectedly, both excitatory and inhibitory synaptic receptor membrane dynamics, content and transmissions are altered by NMDAR or GABAaR mAb, irrespective of the affinity or antagonistic effect of the autoantibodies. The effect of NMDAR mAb on inhibitory synapses and GABAaR mAb on excitatory synapses requires neuronal activity and involves protein kinase signalling. At the cell level, both autoantibodies increase the excitation/inhibition balance of principal cell inputs. Furthermore, NMDAR or GABAaR mAb leads to hyperactivation of hippocampal networks through distinct alterations of principal cell and interneuron properties. Thus, autoantibodies targeting excitatory NMDAR or inhibitory GABAaR trigger convergent network dysfunctions through a combination of shared and distinct mechanisms.

Small extracellular vesicles administered directly in the brain promote neuroprotection and decreased microglia reactivity in a stroke mouse model.

Herein, we investigate the bioactivity of small extracellular vesicles (sEVs), focusing on their local effect in the brain. sEVs from mononuclear cells (MNCs) showed superior effects in vitro to sEVs from mesenchymal stem cells (MSCs) and were able to promote neuroprotection and decrease microglia reactivity in a stroke mouse model.

It takes two to tango: Concerted protein translation and degradation necessary for synaptic scaling.

Synaptic scaling allows neurons to adjust synaptic strength in response to chronic alterations in neuronal activity. A new study in PLOS Biology identifies a pathway that synergizes protein synthesis and degradation with remodeling of the microRNA (miRNA)-induced silencing complex (miRISC) to mediate synaptic scaling.

Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2.

Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan's syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.

Mechanisms of homeostatic plasticity in the excitatory synapse.

Brain development, sensory information processing, and learning and memory processes depend on Hebbian forms of synaptic plasticity, and on the remodeling and pruning of synaptic connections. Neurons in networks implicated in these processes carry out their functions while facing constant perturbation; homeostatic responses are therefore required to maintain neuronal activity within functional ranges for proper brain function. Here, we will review in vitro and in vivo studies demonstrating that several mechanisms underlie homeostatic plasticity of excitatory synapses, and identifying participant molecular players. Emerging evidence suggests a link between disrupted homeostatic synaptic plasticity and neuropsychiatric and neurologic disorders. Hebbian forms of synaptic plasticity, such as long-term potentiation (LTP), induce long-lasting changes in synaptic strength, which can be destabilizing and drive activity to saturation. Conversely, homeostatic plasticity operates to compensate for prolonged activity changes, stabilizing neuronal firing within a dynamic physiological range. We review mechanisms underlying homeostatic plasticity, and address how neurons integrate distinct forms of plasticity for proper brain function. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".