The Ash Twins Blog

In the previous post, I mentioned that our studies in the mouse model for MECP2 duplication syndrome indicate that synapses are being formed and lost at a high, immature rate for the life of the animal, which is associated with the development of stereotyped repetitive behaviors and epileptic seizures.

Achieving a balance between cortical circuit stability and plasticity allows us to adapt to and learn from novel environmental experiences without forgetting useful information from the past. Children and adolescents have little experience to guide their actions, so new information is very important, and plasticity (learning) is favored over stability (memory). Conversely, the elderly have a wealth of past experiences, so incorporating new information into world models is less likely to be beneficial, and stability is favored over plasticity.

One theory for the pathophysiology of developmental brain disorders like Fragile X syndrome, Rett Syndrome, Angelman syndrome, and MECP2 duplication syndrome is that the link between genetic lesions and certain neuropsychiatric phenotypes is an imbalance between stability and plasticity. If the brain’s synapses are too stable, the brain will have trouble adapting to new experiences; Synaptic rigidity of this sort could lead to the permanent infantilism seen in Angelman syndrome, and has indeed been demonstrated Angelman syndrome mouse model. If the brain’s synapses are too labile, on the other hand, extant memories may be continually overturned by new experiences, or even worse synapses will continue to develop past their normal strengths, generating stereotypic behavior and epileptic circuitry. In either case, the cumulative refinement of neural circuitry that is important for brain development cannot occur.

Results in my lab suggest that MECP2 duplication syndrome is an example may be such a syndrome of too much plasticity. In juvenile mice, this bias toward synapse turnover allows relatively rapid acquisition of both adaptive (enhanced motor learning) and maladaptive (enhanced conditioned fear response) environmental adaptations. As the mice reach adulthood, they have sampled a broader range of world states, but the normal developmental deceleration of cortical plasticity which would shift the continuum to stability in cortical circuits does not occur. Instead, circuits oversaturate, leading to hyperexcitable ensembles which continue to self-strengthen by positive feedback. Activity in these dysfunctional cortical circuits produces compulsive, repetitive, stereotyped behaviors as well as runaway resonant excitation and epileptic seizures. Along these lines, it appears that patients steadily acquire developmental milestones until a critical point in which neurodevelopment stagnates and seizures ensue (Karas & Zoghbi, unpublished observations).