Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington’s Disease

Abstract

In the BACHD mouse model of Huntington's disease (HD), deletion of the N17 domain of the Huntingtin gene (BACHDΔN17, Q97) has been reported to lead to nuclear accumulation of mHTT and exacerbation of motor deficits, neuroinflammation and striatal atrophy (Gu et al., 2015). Here we characterized the effect of N17 deletion on dorsolateral striatal medium spiny neurons (MSNs) in BACHDΔN17 (Q97) and BACWTΔN17 (Q31) mice by comparing them to MSNs in wildtype (WT) mice. Mice were characterized on a series of motor tasks and subsequently whole cell patch clamp recordings with simultaneous biocytin filling of MSNs in in vitro striatal slices from these mice were used to comprehensively assess their physiological and morphological features. Key findings include that: Q97 mice exhibit impaired gait and righting reflexes but normal tail suspension reflexes and normal coats while Q31 mice do not differ from WT; intrinsic membrane and action potential properties are altered-but differentially so-in MSNs from Q97 and from Q31 mice; excitatory and inhibitory synaptic currents exhibit higher amplitudes in Q31 but not Q97 MSNs, while excitatory synaptic currents occur at lower frequency in Q97 than in WT and Q31 MSNs; there is a reduced total dendritic length in Q31-but not Q97-MSNs compared to WT, while spine density and number did not differ in MSNs in the three groups. The findings that Q31 MSNs differed from Q97 and WT neurons with regard to some physiological features and structurally suggest a novel role of the N17 domain in the function of WT Htt. The motor phenotype seen in Q97 mice was less robust than that reported in an earlier study (Gu et al., 2015), and the alterations to MSN physiological properties were largely consistent with changes reported previously in a number of other mouse models of HD. Together this study indicates that N17 plays a role in the modulation of the properties of MSNs in both mHtt and WT-Htt mice, but does not markedly exacerbate HD-like pathogenesis in the BACHD model.

K369I Tau Mice Demonstrate a Shift Towards Striatal Neuron Burst Firing and Goal-directed Behaviour

“…This is in part because there is divergence as to the exact differences in electrophysiological properties, the large over-lap and variability in these properties, and the conditions in which these differences are observed (Lepora et al, 2011;Willett et al, 2019). In accordance, electrophysiological studies of rodent striatal neurons (like the current study) do not between distinguish between dMSNs and iMSNs (Fritz et al, 2019;Mao et al, 2019;Gazan et al, 2020;Goodliffe et al, 2020;Willett et al, 2020;Yoo et al, 2020), though it is possible that electrophysiological differences in these pathways, even if subtle, may be important for the overall impact of the K3 mutation.…”

Synaptic Dysfunction in Huntington’s Disease: Lessons from Genetic Animal Models

“…Although animal models of HD have provided a wealth of information regarding synaptic pathology, those models hardly recapitulate the cardinal motor abnormality, chorea. Thus, electrophysiological recordings of the corticostriatal pathway and output structures from models that display chorea, for example, BACHD-ΔN17 mice (Gu and others 2015; however, see Goodliffe and others 2020) or aged tgHD rats, should prove invaluable to understand the mechanisms of this cardinal symptom. In terms of underexplored cell types and circuits in HD models, it will be important to examine the role of additional striatal GABAergic types such as calretinin-, NPY-, and tyrosine hydroxylase (TH)-expressing interneurons.…”