Mitochondrial impairments in the hippocampus of Mecp2 mutant mice.

• RICART K, CALFA G, POZZO-MILLER L, LANDAR

Congreso; Society for Neuroscience International Congress; 2012

Mitochondria are not only necessary for ATP synthesis, but also essential for intracellular Ca 2+ homeostasis and redox signaling cascades. Mitochondrial morphology is dynamic and controlled by balanced fission and fusion events, which are critical to proper mitochondrial function. Rett syndrome is an X-linked neurological disorder that almost exclusively affects girls, being the leading cause of several intellectual disabilities (1:10,000 births). The symptoms include irregularities in motor activity, including gait and motor imbalance and a stereotypic hand movement, altered breathing patterns, continued cognitive decline, and seizures. Intriguingly, some of these RTT features are also present in various mitochondrial disorders. The perception that mitochondrial abnormalities contribute to RTT predates the discovery of mutations in MECP2 as its primary causative factor. Previous studies in Mecp2 mutant mice showed abnormal respiration and impaired activity of mitochondrial complexes of the respiratory chain, further supporting the hypothesis that mitochondrial dysfunction plays a role in RTT. Here, we performed a quantitative analysis of mitochondrial density and morphology at the electron microscopy level in dendrites and axons within hippocampal CA1 stratum radiatum of symptomatic Mecp2 mice (P50-60, “Jaenish” strain) and age-matched wildtype (wt) littermates (3 mice per genotype). The number of mitochondria in a total sampled area of 10,000µm 2 is not significantly different between genotypes (wt 5±0.4 vs. Mecp2 4±0.4 mitochondria per 10µm 2 ; p>0.05). On the other hand, the circularity index of individual mitochondria is significantly different, with more circular mitochondria (index=1) in Mecp2 mutants (wt 0.789±0.0002 n=4,213 vs. Mecp2 0.833±0.0019 n=4,555; p>0.05, K-S test). Consistently, the maximum dimension (wt 0.392±0.004µm vs. Mecp2 0.375±0.003µm; p<0.0001) and perimeter of individual mitochondria (wt1.248±0.011µm vs. Mecp2 1.209±0.0009µm; p<0.00001) were also significantly different (K-S test). These differences in mitochondrial ultrastructure may be due to changes in mitochondrial fusion and fission, which in turn may affect their motility and bioenergetic function. Experiments under way will determine the consequences of Mecp2 deletion on all these mitochondrial parameters. The observed differences in mitochondrial ultrastructure may be related to heightened neuronal activity, as observed in the hyperexcitable hippocampal network of symptomatic Mecp2 mutant mice (Calfa et al. J Neurophysiol 2011).