Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features.

Autoantibodies directed against the GluA3 subunit (anti-GluA3 hIgGs) of AMPA receptors have been identified in 20%-25% of patients with frontotemporal lobar degeneration (FTLD). Data from patients and in vitro/ex vivo pre-clinical studies indicate that anti-GluA3 hIgGs negatively affect glutamatergic neurotransmission. However, whether and how the chronic presence of anti-GluA3 hIgGs triggers synaptic dysfunctions and the appearance of FTLD-related neuropathological and behavioural signature has not been clarified yet. To address this question, we developed and characterized a pre-clinical mouse model of passive immunization with anti-GluA3 hIgGs purified from patients. In parallel, we clinically compared FTLD patients who were positive for anti-GluA3 hIgGs to negative ones. Clinical data showed that the presence of anti-GluA3 hIgGs defined a subgroup of patients with distinct clinical features. In the preclinical model, anti-GluA3 hIgGs administration led to accumulation of phospho-tau in the postsynaptic fraction and dendritic spine loss in the prefrontal cortex. Remarkably, the preclinical model exhibited behavioural disturbances that mostly reflected the deficits proper of patients positive for anti-GluA3 hIgGs. Of note, anti-GluA3 hIgGs-mediated alterations were rescued in the animal model by enhancing glutamatergic neurotransmission with a positive allosteric modulator of AMPA receptors. Overall, our study clarified the contribution of anti-GluA3 autoantibodies to central nervous system symptoms and pathology and identified a specific subgroup of FTLD patients. Our findings will be instrumental in the development of a therapeutic personalised medicine strategy for patients positive for anti-GluA3 hIgGs.

Detrimental effects of soluble α-synuclein oligomers at excitatory glutamatergic synapses.

Introduction: Oligomeric and fibrillar species of the synaptic protein α-synuclein are established key players in the pathophysiology of Parkinson's disease and other synucleinopathies. Increasing evidence in the literature points to prefibrillar oligomers as the main cytotoxic species driving dysfunction in diverse neurotransmitter systems even at early disease stages. Of note, soluble oligomers have recently been shown to alter synaptic plasticity mechanisms at the glutamatergic cortico-striatal synapse. However, the molecular and morphological detrimental events triggered by soluble α-synuclein aggregates that ultimately lead to excitatory synaptic failure remain mostly elusive. Methods: In the present study, we aimed to clarify the effects of soluble α-synuclein oligomers (sOligo) in the pathophysiology of synucleinopathies at cortico-striatal and hippocampal excitatory synapses. To investigate early defects of the striatal synapse in vivo, sOligo were inoculated in the dorsolateral striatum of 2-month-old wild-type C57BL/6J mice, and molecular and morphological analyses were conducted 42 and 84 days post-injection. In parallel, primary cultures of rat hippocampal neurons were exposed to sOligo, and molecular and morphological analyses were performed after 7 days of treatment. Results: In vivo sOligo injection impaired the post-synaptic retention of striatal ionotropic glutamate receptors and decreased the levels of phosphorylated ERK at 84 days post-injection. These events were not correlated with morphological alterations at dendritic spines. Conversely, chronic in vitro administration of sOligo caused a significant decrease in ERK phosphorylation but did not significantly alter post-synaptic levels of ionotropic glutamate receptors or spine density in primary hippocampal neurons. Conclusion: Overall, our data indicate that sOligo are involved in pathogenic molecular changes at the striatal glutamatergic synapse, confirming the detrimental effect of these species in an in vivo synucleinopathy model. Moreover, sOligo affects the ERK signaling pathway similarly in hippocampal and striatal neurons, possibly representing an early mechanism that anticipates synaptic loss.