Deficits in coordinated neuronal activity and network topology are striatal hallmarks in Huntington’s disease

Abstract

Background: Network alterations underlying neurodegenerative diseases often precede symptoms and functional deficits. Thus, their early identification is central for improved prognosis. In Huntington's disease (HD), the corticostriatal networks, involved in motor function processing, are the most compromised neural substrate. However, whether the network alterations are intrinsic of the striatum or the cortex is not fully understood. Results: In order to identify early HD neural deficits, we characterized neuronal ensemble calcium activity and network topology of HD striatal and cortical cultures. We used large-scale calcium imaging combined with activitybased network inference analysis. We extracted collective activity events and inferred the topology of the neuronal network in cortical and striatal primary cultures from wild-type and R6/1 mouse model of HD. Striatal, but not cortical, HD networks displayed lower activity and a lessened ability to integrate information. GABA A receptor blockade in healthy and HD striatal cultures generated similar coordinated ensemble activity and network topology, highlighting that the excitatory component of striatal system is spared in HD. Conversely, NMDA receptor activation increased individual neuronal activity while coordinated activity became highly variable and undefined. Interestingly, by boosting NMDA activity, we rectified striatal HD network alterations. Conclusions: Overall, our integrative approach highlights striatal defective network integration capacity as a major contributor of basal ganglia dysfunction in HD and suggests that increased excitatory drive may serve as a potential intervention. In addition, our work provides a valuable tool to evaluate in vitro network recovery after treatment intervention in basal ganglia disorders.

Unraveling the Spatiotemporal Distribution of VPS13A in the Mouse Brain

“…Cortical primary mouse cultures were performed, as previously described [ 47 ]. Brains from E18.5 embryos were excised and placed in Neurobasal medium (Fisher Scientific, Waltham, MA, USA).…”

Astrocytic and Neuronal Apolipoprotein E Isoforms Differentially Affect Neuronal Excitability

“…Further, astrocytic ApoE4-treated neurons induce a decreased proportion of independent spikes, i.e., spikes outside a burst, after 1 h of treatment compared to ApoE KO-treated neurons ( Figure 2E ). The proportion of independent spikes in a culture is an indicator of spike efficacy and represents isolated and not coordinated activity ( Fernandez-Garcia et al, 2020 ). Reduced percentages of independent spikes within a culture negatively correlate with spike efficacy and network coordination.…”

In Vitro Development of Human iPSC-Derived Functional Neuronal Networks on Laser-Fabricated 3D Scaffolds

“…Spontaneous calcium activity was acquired upon an AxioImager A1 microscope equipped with an AxioCm ICc1 camera and AxioVision software (version 4.8). Recorded data were analyzed using NETCAL (), a Matlab-run software package for the large-scale analysis of calcium imaging experiments in neuronal cultures. , Image sequences of spontaneous activity recordings (of jpeg format) were converted to TIF using the bioformats plugin of Fiji . The main steps of the data analysis pipeline were the following: preprocessing, regions of interest (ROIs) identification, trace extraction, selection of active traces, spike inference, and network inference.…”

“…The community statistic reflects the existence of functional microcircuits and varies between 0 (the whole network is the only functional circuit) and 1 (each single neuron is a functional microcircuit). The detailed description of these quantities and their use in the context of neuronal networks can be found in refs and . Network plots were produced using the Python package NetworkX.…”