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. 2020 May 28;18(1):58.
doi: 10.1186/s12915-020-00794-4.

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

S Fernández-García  1   2   3 , J G Orlandi  4   5 , G A García-Díaz Barriga  1   2   3 , M J Rodríguez  1   2   3 , M Masana  1   2   3 , J Soriano  5   6 , J Alberch  7   8   9   10
Affiliations

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

S Fernández-García et al. BMC Biol. .

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 cortico-striatal 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 activity-based 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. GABAA 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.

Keywords: Calcium imaging; Huntington’s disease; Network; Neuronal activity; Striatum.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Spontaneously active neurons and coordinated ensemble activity were reduced specifically in the striatum, but not the cortex, of primary cultures from the R6/1 HD model (HD) compared to wild-type (WT). a Primary cultures were obtained from the striatum and cortex of E18 WT and HD mouse embryos, and neuronal spontaneous activity was measured using fluorescence calcium imaging at 15 DIV. b Representative average fluorescence trace and reconstructed spikes from neurons are represented in raster plots for WT (top) and HD (bottom) for striatal (STR, left) and cortical (CTX, right) cultures. Vertical blue bars highlight network bursts. c Percentage of active neurons in the cultures. d Percentage of active neurons that participate in spontaneous network burst. e Average network inter-burst interval (IBI), i.e., the average time between consecutive network bursts. f Global activity rate of the cultures, i.e., total number of spikes per unit time within the field of view. g Fraction of independent spikes, i.e., those spikes not followed or preceded by any other spike within 50 ms in the whole system. c–g Each circle in the plot represents a single culture from at least three different litters (c, f, g: STR WT n = 38; STR HD n = 37; CTX WT n = 19; CTX HD n = 22) (d, e: STR WT n = 22; STR HD n = 16; CTX WT n = 19; CTX HD n = 22), thick line the mean, thick shaded area the standard error of the mean, and thin shaded area the standard deviation. Statistical analysis was performed using two-sample Student’s t test between WT and HD populations, *p < 0.05, **p < 0.01
Fig. 2
Fig. 2
Network topology properties of striatal, but not cortical, cultures are altered in HD. a Representative effective connectivity matrix of a neuronal culture. Each dot represents an effective connection from neuron to neuron, i.e., neuron i → neuron j. Communities were identified using the Louvain community detection algorithm and are highlighted in color. Connections between neurons that belong to the same community (module) are intra-modular effective connections, while effective connections between neurons not belonging to the same community are inter-modular connections. b Representative effective connectivity matrices of WT and HD striatal and cortical neuronal cultures. c–f Network topology properties for WT and HD striatal and cortical cultures under basal conditions. c Global efficiency, i.e., average of the inverse shortest path length. d Average community size, i.e., average number of neurons per module. e Community statistic Q. f Average number of connector hubs, i.e., large neuronal nodes that connect mostly with nodes from other communities. Each circle represents a single experiment (STR WT n = 29; STR HD n = 24; CTX WT n = 19; CTX HD n = 22), thick line the mean, thick shaded area the standard error of the mean, and thin shaded area the standard deviation. Statistical analysis was performed using two-sample Student’s t test between WT and HD populations, *p < 0.05
Fig. 3
Fig. 3
GABAA receptor blockade with bicuculline (BIC) differentially induces network burst events in striatal cultures of WT or HD. a Spontaneous neuronal activity was recorded during 10 min in basal conditions and after addition of bicuculline (BIC, 60 μM). The plots show representative average fluorescence trace, and reconstructed spikes from neurons are represented in raster plots for WT (top) and HD (bottom) for baseline (left) and after system wide disinhibition with BIC 60 (right). Vertical blue bars highlight network bursts. b Percentage of active neurons before and after the addition of BIC. c Percentage of active neurons participating in network bursts before and after the addition of BIC and d average inter-burst interval (IBI). e Global activity rate of the cultures. f Fraction of independent spikes. Each circle represents a single experiment (b, e, f: STR WT n = 11; STR HD n = 10; CTX WT n = 19; CTX HD n = 22) (c, d: STR WT n = 4; STR HD n = 5; CTX WT n = 19; CTX HD n = 22), thick line the mean, thick shaded area the standard error of the mean, and thin shaded area the standard deviation. Statistical analysis was performed using mixed ANOVA and posterior post hoc test with Bonferroni’s multiple comparison correction. Only * for post hoc test are shown, *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 4
Fig. 4
Disinhibition shapes different network properties in WT or HD mouse models. a Representative examples of WT and HD striatal effective connectivity matrices after disinhibition with BIC 60 μM. Color boxes highlight communities. b–e Change in network properties for cultures before and after disinhibition. b Global efficiency, c average community size, d community statistic Q, and e average number of connector hubs. Each circle represents a single experiment (STR WT n = 8; STR HD n = 9; CTX WT n = 19; CTX HD n = 22), thick line the mean, thick shaded area the standard error of the mean, and thin shaded area the standard deviation. Statistical analysis was performed using mixed ANOVA and posterior post hoc test with Bonferroni’s multiple comparison correction. Only * for the post hoc test are shown, *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 5
Fig. 5
NMDA rises global neuronal activity in WT and HD striatal primary cultures. a Experiment timeline. Spontaneous neuronal activity was recorded during 10 min in basal conditions and after addition of 10 μM NMDA + 10 μM glycine. b Percentage of active neurons. c Representative raster plots of spikes and average fluorescence trace before (left) and after (right) addition of NMDA for WT (upper) and HD (lower). d Global activity rate of the cultures and e fraction of independent spikes. Each circle represents a single experiment (STR WT n = 10; STR HD n = 10), thick line the mean, thick shaded area the standard error of the mean, and thin shaded area the standard deviation. Statistical analysis was performed using mixed ANOVA and posterior post hoc test with Bonferroni’s multiple comparison correction. Only * for the post hoc test are shown, *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 6
Fig. 6
NMDA treatment restores neuronal network topology in striatal HD cultures. a Representative examples of WT and HD striatal effective connectivity matrices after NMDA 10 μM. Color boxes highlight communities. b–e Change in network properties for cultures before and after NMDA treatment. b Global efficiency, c average community size, d community statistic Q, and e average number of connector hubs. Each circle represents a single experiment (STR WT n = 10; STR HD n = 7), thick line the mean, thick shaded area the standard error of the mean, and thin shaded area the standard deviation. Statistical analysis was performed using mixed ANOVA and posterior post hoc test with Bonferroni’s multiple comparison correction. Only * for the post hoc test are shown, *p < 0.05, **p < 0.01, ***p < 0.001
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