The burden of disease for myotonic dystrophy (DM) is multi-systemic, including skeletal muscle weakness, fatigue, cardiac arrhythmias, respiratory insufficiency and intellectual disability. Modeling of this constellation of symptoms is important for mechanistic studies and preclinical therapy development. Yet, what is arguably the most widely available mouse model, the HSA-LR, is designed to model the skeletal muscle molecular, structural and functional deficits of skeletal muscle.

Dr. Guey-Shin Wang and colleagues at Academia Sinica (Taiwan) developed an EpA960/CaMKII-Cre mouse that carries an inducible human DMPK with 960 CTG repeats in the 3’ UTR. Cre expression occurs in the forebrain (cortex and hippocampus) after two weeks of age, preserving earlier neurodevelopmental events from toxic RNA exposure and MBNL depletion.

Atrophy of the cortex and corpus callosum, features of the myotonic dystrophy type 1 (DM1) patient central nervous system (CNS), were observed in the adult EpA960/CaMKII-Cre mice. The mice showed progressive neuropathological findings: reduced MBNL1 in dendrites of cortical layer V neurons at six months of age, brain atrophy (axon and dendrite pathology) by nine months, and loss of MBNL2 and MBNL-directed splicopathy were later events, at 12 months.

Functionally, EpA960/CaMKII-Cre mice were evaluated at six months for hippocampus-dependent spatial learning and memory using the Morris water maze—escape latencies were greater for mutants compared with controls, suggestive of slower learning. Evaluation of long-term potentiation (LTP) in hippocampal slices at six months of age also was consistent with synaptic dysfunction and the functional learning disabilities seen in these mice.

The EpA960/CaMKII-Cre mouse model recapitulates some features, including disease progression, seen in DM1 patient CNS. Moreover, the authors suggest that depletion of MBNL1 and MBNL2 in the CNS are distinct events with differing roles in disease progression. Early synaptic dysfunction may be triggered by MBNL1 depletion, and is a precursor to dendritic and axonal pathology. Since splicing changes were detected only later, commensurate with MBNL2 depletion, the early synaptic dysfunction likely is mediated by MBNL1-related, but alternative splicing-independent events.

Reference:

Reduced Cytoplasmic MBNL1 is an Early Event in a Brain-specific Mouse Model of Myotonic Dystrophy.
Wang PY, Lin YM, Wang LH, Kuo TY, Cheng SJ, Wang GS.
Hum Mol Genet. 2017 Mar 24. doi: 10.1093/hmg/ddx115.