Loss of Homeostasis in the Direct Pathway in a Mouse Model of Asymptomatic Parkinson's Disease

Abstract

The characteristic slowness of movement in Parkinson's disease relates to an imbalance in the activity of striatal medium spiny neurons (MSNs) of the direct (dMSNs) and indirect (iMSNs) pathways. However, it is still unclear whether this imbalance emerges during the asymptomatic phase of the disease or if it correlates with symptom severity. Here, we have used in vivo juxtacellular recordings and transgenic mice showing MSN-type-specific expression of fluorescent proteins to examine striatal imbalance after lesioning dopaminergic neurons of the substantia nigra. Multivariate clustering analysis of behavioral data discriminated 2 groups of dopamine-lesioned mice: asymptomatic (42 Ϯ 7% dopaminergic neuron loss) and symptomatic (85 Ϯ 5% cell loss). Contrary to the view that both pathways have similar gain in control conditions, dMSNs respond more intensely than iMSNs to cortical inputs in control animals. Importantly, asymptomatic mice show significant functional disconnection of dMSNs from motor cortex without changes in iMSN connectivity. Moreover, not only the gain but also the timing of the pathways is altered in symptomatic parkinsonism, where iMSNs fire significantly more and earlier than dMSNs. Therefore, cortical drive to dMSNs decreases after partial nigrostriatal lesions producing no behavioral impairment, but additional alterations in the gain and timing of iMSNs characterize symptomatic rodent parkinsonism.

Differential enhancement of ERK, PKA and Ca2+ signaling in direct and indirect striatal neurons of Parkinsonian mice

“…These observations confirmed and expanded previous reports in anaesthetized rodents (Mallet et al, 2006). The increased basal activity of iSPNs in vivo is attributed to their enhanced sensitivity to cortical inputs (Escande et al, 2016;Mallet et al, 2006;Ryan et al, 2018). In our slice study we observed an increase in AMPA-induced intracellular Ca 2+ responses specifically in iSPNs of lesioned mice, without change in dSPN.…”

Indirect Medium Spiny Neurons in the Dorsomedial Striatum Regulate Ethanol-Containing Conditioned Reward Seeking

“…A 2A R is known to coexpress with D 2 R in the striatal iMSNs (Farrell et al, 2013; Oude Ophuis et al, 2014), so we used D 2 R promoter-driven eGFP-expressing mice (Escande et al, 2016) to investigate whether A 2A R activation and operant conditioning with the conditioned reward change iMSNs activities in the DMS (Fig. 5A).…”

Striatal synapses, circuits, and Parkinson's disease

“…In addition to these adaptations in intrinsic excitability, synaptic homeostatic plasticity is also engaged: iSPNs undergo substantial spine pruning in PD models [15*,16–18]. However, unlike the situation in hippocampus, there is no obvious synaptic scaling; in fact, the strength of the remaining synapses is increased [15•,19,20]. This may be due, at least in part, to the fact that the loss of D2R signaling promotes LTP by dis-inhibiting A2a receptor (A2aR) signaling [21], which may disrupt scaling mechanisms.…”