Reconstituting Corticostriatal Network on-a-Chip Reveals the Contribution of the Presynaptic Compartment to Huntington’s Disease

Abstract

Huntington's disease (HD), a devastating neurodegenerative disorder, strongly affects the corticostriatal network, but the contribution of pre- and postsynaptic neurons in the first phases of disease is unclear due to difficulties performing early subcellular investigations in vivo. Here, we have developed an on-a-chip approach to reconstitute an HD corticostriatal network in vitro, using microfluidic devices compatible with subcellular resolution. We observed major defects in the different compartments of the corticostriatal circuit, from presynaptic dynamics to synaptic structure and transmission and to postsynaptic traffic and signaling, that correlate with altered global synchrony of the network. Importantly, the genetic status of the presynaptic compartment was necessary and sufficient to alter or restore the circuit. This highlights an important weight for the presynaptic compartment in HD that has to be considered for future therapies. This disease-on-a-chip microfluidic platform is thus a physiologically relevant in vitro system for investigating pathogenic mechanisms and for identifying drugs.

Huntingtin phosphorylation governs BDNF homeostasis and improves the phenotype of Mecp2 knockout mice

“…1A and Movie EV1). The dynamics of vesicles are in agreement with our recent studies using this technology (Virlogeux et al, 2018;Moutaux et al, 2018).…”

“…Cortical neurons plated in the first compartment extend axons that connect to striatal dendrites within the synaptic compartment ( Fig. 1A), thus creating an oriented corticostriatal network on-a-chip (Virlogeux et al, 2018). This network reproduces the physiological network as we previously showed that cortical neurons from embryonic day (E)15.5 are enriched in CTIP2/TBR1 neurons that correspond to the deepest layers of the cortex that send axons to the striatum.…”

“…This network reproduces the physiological network as we previously showed that cortical neurons from embryonic day (E)15.5 are enriched in CTIP2/TBR1 neurons that correspond to the deepest layers of the cortex that send axons to the striatum. Also, most striatal neurons correspond to enkephalin-positive neurons that are the output-projecting neurons of the striatum (Virlogeux et al, 2018). Cortical neurons were transduced with mCherry-tagged BDNF lentivirus (BDNF-mCherry) and we used spinning disk confocal videomicroscopy to record the dynamics of BDNF-mCherry containing vesicles within microchannels in the axons ( Fig.…”

Enhanced striatopallidal gamma‐aminobutyric acid (GABA)A receptor transmission in mouse models of huntington's disease

“…When mice begin to exhibit sensory-motor impairment, iSPNs manifest a deficit in corticostriatal synaptic function that is attributable to a reduction in the release of brain derived neurotrophic factor and its activation of postsynaptic tropomyosin receptor kinase B receptors. [16][17][18] This deficit is paralleled by a reduction in dendritic excitability of iSPNs (unpublished observations). As axospinous cortical synapses constitute the principal source of excitatory drive to normally quiescent iSPNs, these changes suggest that the indirect pathway becomes hypoexcitable in the early stages of HD.…”

“…There are parallels in the evolution of striatal pathology in animal models of HD. When mice begin to exhibit sensory‐motor impairment, iSPNs manifest a deficit in corticostriatal synaptic function that is attributable to a reduction in the release of brain derived neurotrophic factor and its activation of postsynaptic tropomyosin receptor kinase B receptors . This deficit is paralleled by a reduction in dendritic excitability of iSPNs (unpublished observations).…”