Since the identification of the gene responsible for HD (Huntington's disease), many genetic mouse models have been generated. Each employs a unique approach for delivery of the mutated gene and has a different CAG repeat length and background strain. The resultant diversity in the genetic context and phenotypes of these models has led to extensive debate regarding the relevance of each model to the human disorder. Here, we compare and contrast the striatal synaptic phenotypes of two models of HD, namely the YAC128 mouse, which carries the full-length huntingtin gene on a yeast artificial chromosome, and the CAG140 KI (knock-in) mouse, which carries a human/mouse chimaeric gene that is expressed in the context of the mouse genome, with our previously published data obtained from the R6/2 mouse, which is transgenic for exon 1 mutant huntingtin. We show that striatal MSNs (medium-sized spiny neurons) in YAC128 and CAG140 KI mice have similar electrophysiological phenotypes to that of the R6/2 mouse. These include a progressive increase in membrane input resistance, a reduction in membrane capacitance, a lower frequency of spontaneous excitatory postsynaptic currents and a greater frequency of spontaneous inhibitory postsynaptic currents in a subpopulation of striatal neurons. Thus, despite differences in the context of the inserted gene between these three models of HD, the primary electrophysiological changes observed in striatal MSNs are consistent. The outcomes suggest that the changes are due to the expression of mutant huntingtin and such alterations can be extended to the human condition.
Keywords: ACSF, artificial cerebrospinal fluid; AP5, dl-2-amino-5-phosphonovaleric acid; BIC, bicuculline methobromide; CAG 140 knock-in mouse model; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; EPSC, excitatory postsynaptic current; GABAA, γ-aminobutyric acid type A; HD, Huntington's disease; HF, high frequency; Huntington's disease; IPSC, inhibitory postsynaptic current; KI, knock-in; LF, low frequency; MSN, medium-sized spiny neuron; WT, wild-type; YAC128 mouse model; electrophysiology; striatum.