Biology subjects

Ruggieri, S.

Publications and source records attributed to Ruggieri, S..

5 recordsLinked to original sources

bioRxiv2026

Short-term plasticity at retinogeniculate synapses depends on synaptic strength

Relay neurons of the dorsal lateral geniculate nucleus (dLGN) receive convergent inputs from retinal ganglion cells (RGCs). Retinogeniculate synapses exhibit a highly skewed distribution of synaptic strength, with a few strong inputs and many weak ones. Strong synapses are thought to dominate relay neuron activity. However, the contribution of individual inputs might not just depend on strength but also on short-term plasticity Using minimal stimulation recordings in acute mouse brain slices, we analyzed the electrophysiological properties of individual retinogeniculate synapses. We observed a robust inverse correlation between synaptic strength and short-term plasticity: weak synapses showed facilitation, whereas strong synapses exhibited pronounced depression. This was consistent with increasing vesicle release probability and enhanced AMPA receptor desensitization at stronger synapses. Analysis of synaptic current kinetics further suggested that variability in synaptic strength reflects not only differences in synapse size and AMPA receptor content but also differences in the electrotonic distance of synapses from the soma. Together, these results reveal systematic heterogeneity in both presynaptic and postsynaptic properties of retinogeniculate synapses. Therefore, the relative contribution of weak and strong inputs to relay neuron firing is likely activity-dependent, with strong synapses dominating when RGCs fire few action potentials and weaker inputs contributing more during sustained or high-frequency firing with several action potentials.

neuroscience↗

bioRxiv2024

AMPA receptor desensitization shapes gain control in the lateral geniculate nucleus

Synaptic short-term plasticity and EPSP summation determine the processing of visual information by dLGN relay cells. In vitro studies suggested that desensitization of AMPA receptor results in pronounced short-term depression in retinogeniculate synapses thereby influencing activation of relay cells by retinal ganglion cell spikes. However, whether retinogeniculate synapses depress and whether AMPA receptors desensitize in vivo is controversial. We here tested the role of AMPA receptor desensitization in processing of visual information by generating a computational model of a dLGN relay cell containing AMPA receptors with different levels of desensitization. In addition, we investigated the in vivo activity of dLGN relay cells in wildtype and CKAMP44-/- mice. CKAMP44 is an auxiliary subunit that increases desensitization of AMPA receptors in retinogeniculate synapses. The comparison of responses of relay cells in the two genotypes therefore allowed us to obtain information about the contribution of AMPA receptor desensitization in processing of visual information. The simulations and the in vivo data show that AMPA receptor desensitization affects relay cell activity by decreasing input gain and response gain. In addition, desensitization sharpens the response of relay neurons to moving gratings in the temporal domain by decreasing the firing rate when the non-preferred stimulus is presented. Altogether, we uncover a complex role of CKAMP44 and AMPA receptor desensitization in information processing of dLGN relay neurons in vivo.

neuroscience↗

bioRxiv2019

Accelerated brain ageing and disability in multiple sclerosis

BackgroundBrain atrophy occurs in both normal ageing and in multiple sclerosis (MS), but it occurs at a faster rate in MS, where it is the major driver of disability progression. Here, we employed a neuroimaging biomarker of structural brain ageing to explore how MS influences the brain ageing process.\n\nMethodsIn a longitudinal, multi-centre sample of 3,565 MRI scans in 1,204 MS/clinically isolated syndrome (CIS) patients and 150 healthy controls (HCs) (mean follow-up time: patients 3*41 years, HCs 1*97 years) we measured brain-predicted age using T1-weighted MRI. Brain-predicted age difference (brain-PAD) was calculated as the difference between the brain-predicted age and chronological age. Positive brain-PAD indicates a brain appears older than its chronological age. We compared brain-PAD between MS/CIS patients and HCs, and between disease subtypes. In patients, the relationship between brain-PAD and Expanded Disability Status Scale (EDSS) at study entry and over time was explored.\n\nFindingsAdjusted for age, sex, intracranial volume, cohort and scanner effects MS/CIS patients had markedly older-appearing brains than HCs (mean brain-PAD 11*8 years [95% CI 9*1--14*5] versus -0*01 [-3*0--3*0], p<0*0001). All MS subtypes had greater brain-PAD scores than HCs, with the oldest-appearing brains in secondary-progressive MS (mean brain-PAD 18*0 years [15*4--20*5], p<0*05). At baseline, higher brain-PAD was associated with a higher EDSS, longer time since diagnosis and a younger age at diagnosis. Brain-PAD at study entry significantly predicted time-to-EDSS progression (hazard ratio 1*02 [1*01--1*03], p<0*0001): for every 5 years of additional brain-PAD, the risk of progression increased by 14*2%.\n\nInterpretationMS increases brain ageing across all MS subtypes. An older-appearing brain at baseline was associated with more rapid disability progression, suggesting brain-age could be an individualised prognostic biomarker from a single, cross-sectional assessment.\n\nFundingUK MS Society; National Institute for Health Research University College London Hospitals Biomedical Research Centre.

neuroscience↗

bioRxiv2017

Progression of regional grey matter atrophy in multiple sclerosis

Grey matter atrophy is present from the earliest clinical stages of multiple sclerosis (MS), but the temporal ordering is poorly understood. We aimed to determine the sequence in which grey matter regions become atrophic in MS, and its association with disability accumulation.\n\nIn this longitudinal study, we included 1,417 subjects: 253 with clinically-isolated syndrome (CIS), 708 relapsing-remitting MS (RRMS), 128 secondary-progressive MS (SPMS), 125 primary-progressive MS (PPMS), and 203 healthy controls from 7 European centres. Subjects underwent repeated MRI scanning (total number of scans 3,604); the mean follow-up for patients was 2.41yrs (SD{+/-}1.97). Disability was scored using the Expanded Disability Status Scale (EDSS). We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template. We used an established data-driven event-based model (EBM) to determine the sequence of occurrence of atrophy and its uncertainty. We assigned each subject to a specific EBM stage, based on the number of their atrophic regions. We used nested linear mixed-effects regression models to explore the associations between the rate of increase in the EBM stages over time, disease duration and annual rate of EDSS gain.\n\nThe first regions to become atrophic in CIS and relapse-onset MS patients (RRMS and SPMS) were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus. The sequence of atrophy in PPMS showed a similar involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in relapse-onset MS and late atrophy in PPMS. Patients with SPMS showed the highest EBM stages (highest number of atrophic regions, all p<0.001) at study entry. Rates of increase in EBM stages were significantly different from healthy controls in all MS phenotypes, except for CIS. The increase in the number of atrophic regions (EBM stage) was associated with disease duration in all patients. EBM stage was associated with disability accumulation in RRMS independent of disease duration (p<0.0001).\n\nThis data-driven staging of atrophy progression in a large MS sample demonstrates that grey matter atrophy spreads to involve more regions over time. The sequence in which regions become atrophic is reasonably consistent across MS phenotypes. The spread of atrophy was associated with disease duration, and disability accumulation in RRMS.\n\nAbbreviations

neuroscience↗

bioRxiv2017

Deep grey matter volume loss drives disability worsening in multiple sclerosis

ObjectiveGrey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.\n\nMethodsWe analysed 3,604 brain high-resolution T1-weighted MRI scans from 1,417 participants: 1,214 MS patients (253 clinically-isolated syndrome[CIS], 708 relapsingremitting[RRMS], 128 secondary-progressive[SPMS], 125 primary-progressive[PPMS]), over an average follow-up of 2.41 years (standard deviation[SD]=1.97), and 203 healthy controls (HCs) [average follow-up=1.83 year, SD=1.77], attending 7 European centres. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression.\n\nResultsSPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio=0.73, 95% CIs 0.65, 0.82; p<0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%)[p<0.01]. The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%) (all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta=0.04, p<0.001).\n\nInterpretationThis large multi-centre and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.

neuroscience↗