Biology subjects

Avoli, M.

Publications and source records attributed to Avoli, M..

3 recordsLinked to original sources

bioRxiv2023

Excitatory neuron-specific suppression of the integrated stress response pathway contributes to autism-related phenotypes in a mouse model of fragile X syndrome

Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2 phosphorylation (p-eIF2), is suppressed in excitatory but not inhibitory neurons in a mouse model of fragile X syndrome (FXS; Fmr1-/y). We further show that the decrease in p-eIF2 is mediated via activation of the mTORC1. Genetic reduction of p-eIF2 only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like behavior. In Fmr1-/y mice, genetic restoration of p-eIF2 solely in excitatory neurons reverses elevated protein synthesis and rescues autism-related phenotypes. Thus, we reveal a previously unknown causal relationship between excitatory neuron-specific translational control via the ISR pathway, general protein synthesis and core phenotypes reminiscent of autism in a mouse model of FXS.

neuroscience↗

bioRxiv2021

Sensory processing dysregulations as reliable translational biomarkers in SYNGAP1 haploinsufficiency

Amongst the numerous genes associated with intellectual disability, SYNGAP1 stands out for its frequency and penetrance of loss-of-function variants found in patients, as well as the wide range of co-morbid disorders associated with its mutation. Most studies exploring the pathophysiological alterations caused by Syngap1 haploinsufficiency in mouse models have focused on cognitive problems and epilepsy, however whether and to what extent sensory perception and processing are altered by Syngap1 haploinsufficiency is less clear. By performing EEG recordings in awake mice, we identified specific alterations in multiple aspects of auditory and visual processing, including increased baseline gamma oscillation power, increased theta/gamma phase amplitude coupling following stimulus presentation and abnormal neural entrainment in response to different sensory modality-specific frequencies. We also report lack of habituation to repetitive auditory stimuli and abnormal deviant sound detection. Interestingly, we found that most of these alterations are present in human patients as well, thus making them strong candidates as translational biomarkers of sensory-processing alterations associated with SYNGAP1/Syngap1 haploinsufficiency.

neuroscience↗

bioRxiv2017

Role of KCC2-Dependent Potassium Efflux in 4-Aminopyridine-Induced Epileptiform Synchronization

A balance between excitation and inhibition is required to maintain stable brain network dynamics. Traditionally, seizure activity is believed to arise from the breakdown of this delicate balance in favor of excitation with loss of inhibition. Surprisingly, recent experimental evidence suggests that this conventional view may be untrue, and that inhibition plays a prominent role in the development of epileptiform synchronization. Here, we explored the role of the co-transporter KCC2 in the onset of inhibitory network-induced seizures. Our experiments in acute mouse brain slices of either sex revealed that optogenetic stimulation of either parvalbumin- or somatostatin-expressing interneurons induced ictal discharges in rodent entorhinal cortex during 4-aminopyridine application. These data point to a proconvulsive role of GABAA receptor signaling that is independent of the inhibitory input location (i.e., dendritic vs. somatic). Further, we developed a biophysically realistic network model implementing complex dynamics of the ion concentrations to explore the mechanisms leading to inhibitory network-induced seizures. In agreement with experimental results, we found that stimulation of inhibitory interneurons induced seizure-like activity in a network with reduced potassium A-current. Model predicted that interneuron stimulation triggered interneuron firing that was accompanied by an increase in intracellular chloride and a subsequent KCC2-dependent gradual accumulation of extracellular potassium promoting epileptiform ictal activity. When the KCC2 activity was reduced, stimulation of the interneurons was no longer able to induce ictal events. Overall, our study provides evidence for a proconvulsive role of GABAA receptor signaling that depends on the involvement of the KCC2 co-transporter.

neuroscience↗