Collapse of complexity of brain and body activity due to excessive inhibition and MeCP2 disruption

Complex body movements require complex dynamics and coordination among neurons in motor cortex. Conversely, a long-standing theoretical notion supposes that if many neurons in motor cortex become excessively synchronized, they may lack the necessary complexity for healthy motor coding. However, direct experimental support for this idea is rare and underlying mechanisms are unclear. Here we recorded three-dimensional body movements and spiking activity of many single neurons in motor cortex of rats with enhanced synaptic inhibition and a transgenic rat model of Rett syndrome (RTT). For both cases, we found a collapse of complexity in the motor system. Reduced complexity was apparent in lower-dimensional, stereotyped brain–body interactions, neural synchrony, and simpler behavior. Our results demonstrate how imbalanced inhibition can cause excessive synchrony among movement-related neurons and, consequently, a stereotyped motor code. Excessive inhibition and synchrony may underlie abnormal motor function in RTT.

A diverse and complex repertoire of body movements requires diverse and complex neural activity among cortical neurons. Moreover, interactions between movement-related neurons and the body must be sufficiently high dimensional to carry these movement signals with high fidelity. The complexity of movement-related neural activity and neuron–body interactions can be compromised if synchrony among neurons is excessive. Indeed, it is well understood theoretically that excessive correlations can limit the information capacity of any neural code (1–3)—if all neurons are perfectly synchronized, then different neurons cannot encode different motor signals. Synchrony is also known to play a role in pathophysiology of movement-related disorders, like Parkinson’s disease (4–6). However, synchrony and correlations also contribute to healthy function in the motor system (7–14). For instance, particular groups of synchronized neurons seem to send control signals to particular muscle groups (7, 8) and propagation of correlated firing contributes to motor planning (10). Synchrony can also play a role in motor learning (12–14). These findings suggest that correlated activity among specific subsets of neurons encodes specific motor functions. Thus, it stands to reason that if this synchrony became less selective and more stereotyped across neurons, then the motor code would become less complex and lose specificity, resulting in compromised motor function.Here we explored this possibility in rats, in the caudal part of motor cortex where neurons associated with hindlimb, forelimb, and trunk body movement are located (15–17). We focused on two conditions. First, we studied a transgenic rat model of Rett syndrome (RTT), which has disrupted expression of the MeCP2 gene. Second, we studied normal rats with acutely altered inhibitory neural interactions. Both of these cases are associated with abnormal motor behavior and, possibly, abnormal synchrony. Abnormal synchrony is a possibility, because both of these cases are linked to an imbalance between excitatory (E) and inhibitory (I) neural interactions, which in turn is likely to result in abnormal synchrony. For instance, many computational models suggest that synchrony is strongly dependent on E/I interactions (18–21). Likewise, in experiments, pharmacological manipulation of E/I causes changes in synchrony (19, 22, 23) and the excessive synchrony that occurs during epileptic seizures is often attributed to an E/I imbalance (24, 25). Similarly, the majority of people with RTT suffer from seizures (26) and many previous studies establish E/I imbalance as a common problem in RTT (27). MeCP2 dysfunction, which is known to cause RTT, seems to be particularly important in inhibitory neurons (28). For instance, two studies have shown that disrupting MeCP2 only in specific inhibitory neuron types can recapitulate the effects of brain-wide disruption of MeCP2 (29, 30). However, whether the E/I imbalance favors E or I at the population level seems to vary across different brain regions in RTT. Studies of visual cortex (29) and hippocampus (31) suggest that the balance tips toward too much excitation (perhaps explaining the prevalence of seizures), while studies of somatosensory cortex (32, 33) and a brain-wide study of Fos expression (34) suggest that frontal areas, including motor cortex, are tipped toward excessive inhibition. These facts motivated our choice to study pharmacological disruption of inhibition here. While it is clear that E/I imbalance is important in RTT, it is much less clear how it manifests at the level of dynamics and complexity of neural activity that is responsible for coordinating body movements. Thus, in addition to pursuing the general questions about synchrony and complexity in the motor system discussed above, a second goal of our work was to improve understanding of motor dysfunction due to MeCP2 disruption.Taken together, these facts led us to the following questions: How does MeCP2 disruption impact the complexity of body movements, movement-related neural activity, and motor coding? Are abnormalities in the MeCP2-disrupted motor system consistent with excessive inhibition in motor cortex? We hypothesized that both MeCP2 disruption and excessive inhibition lead to reduced complexity of interactions between cortical neurons and body movements, excessive cortical synchrony, and reduced complexity of body movements. Our findings confirmed this hypothesis and suggest that RTT-related motor dysfunction may be due, in part, to excessive synchrony and inhibition in motor cortex.