P314 Neural compensation drives functional resilience in a cerebellar model of schizophrenia

Alberto A. Vergani*1, Pawan Faris1, Claudia Casellato1, Marialaura De Grazia1and Egidio U. D'Angelo1,2

1Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
2Digital Neuroscience Center, IRCCS Mondino Foundation, Pavia, Italy

*Email: albertoarturo.vergani@unipv.it

Introduction

Schizophrenia (SZ) affects ~1% of the global population (~24 million) [1]. While cortical and subcortical alterations are well-documented, the cerebellum’s role in cognitive dysfunction (CAS) remains underexplored [2]. SZ-related cerebellar degeneration involves neuron loss, reduced dendritic complexity, and weakened connectivity [3], often countered by compensatory hyperconnectivity [4-8]. Following the 'cognitive dysmetria' hypothesis [9], this study quantifies structural and functional changes in a cerebellar network model under atrophy and compensatory synaptogenesis [10-11].


Methods
Using Brain Scaffold Builder (BSB, [12]), we implemented an atrophy algorithm in a mouse cerebellum model, modulating cellular and network changes via the Atrophy Factor (AF, 0–60%).By preserving electrical cell properties, it simulated schizophrenic neurodegeneration while ensuring anatomical plausibility. Atrophy induced morphological shrinkage, dendritic pruning, radius reduction, neural density loss, and cortical thinning. Changes were quantified via apoptosis, dendritic complexity index (DCI, [13]), and connectivity metrics. Compensation via synaptogenesis increased synapse count with AF. The altered connectome (~30K neurons, EGLIF, [14]) was simulated in NEST [15] under baseline conditions (4 Hz mossy fiber stimulation) to assess firing rate changes.

Results
Atrophy altered network structure, reducing neurons, dendritic complexity, connectivity, and synapse count. Compensation offset this by increasing synapses in survived neuron pairs. Functional changes emerged from structural alterations, with excitability rising, reversing at ~10% AF, and zero-crossing at ~25% AF. Granule and Golgi cells showed opposite trends, while Purkinje, stellate, and basket cells were similar in firing change. DCN-I neurons gradually reduced activity, with compensation lightly delaying decline. DCN-P exhibited the highest resilience until ~25% AF, where compensation collapsed, triggering a firing surge disrupting output to telencephalon.

Discussion
This study examined cerebellar network degeneration while preserving electrical properties, highlighting structural changes, synaptic reorganization, and atrophy-related firing dynamics.Synaptic compensation mitigates pathology-driven neuronal damage, with a transition from hyper- to hypo-excitability, particularly in DCN-P, resembling Stern’s inflection point in neurodegenerative resilience [16]. Future work will explore atrophy-compensation effects on stimulus decoding and learning (eye blink conditioning, [17]), integrate with The Virtual Brain [18], compare with MEA recordings [19], and test therapeutic strategies like TMS and pharmacological interventions to enhance cognitive reserve.





Acknowledgements
Work supported by #NEXTGENERATIONEU (NGEU) and funded by MUR, National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) – A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). The VBT Project has received funding from the European Union's Research and Innovation Program Horizon Europe under grant agreement No 101137289.
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