Neural network alterations in Rett Syndrome

Rett syndrome is a devastating neurological disorder. It represents the second leading cause of intellectual disability in females. Symptoms appear around the first birthday when girls lose their acquired language and motor skills. The condition becomes progressively worse with the appearance of cognitive deficits, seizures and worsening of motor function. Rett syndrome is caused by mutations in a protein called MeCP2. Mouse models of Rett syndrome that lack MeCP2 have been generated. These mice develop symptoms that resemble those seen in patients. Studies in mice have also shown that Rett syndrome is a reversible disorder. If we can understand the function of MeCP2 in the brain, then maybe we can identify treatments of Rett syndrome. Although these mouse models have allowed us to study the function of MeCP2, the mechanisms by which loss of MeCP2 leads to Rett syndrome are poorly understood.

The brain organises information through the activity of millions of neurons. These neurons make connections with thousands of other neurons. These neurons communicate with one another at a synapse. We can visualise neurons working together by examining patterns of neuronal oscillations, or brainwaves. Gamma oscillations are an example of a specialised type of neuronal oscillation. These oscillations play important roles in cognitive functions. We wanted to explore whether mouse models of Rett syndrome show changes in the level of gamma oscillations in the brain. In particular, we will examine gamma oscillations in the hippocampus, a region of the brain involved in memory.

The goal of this proposal is to examine how gamma oscillations are affected in mouse models of Rett syndrome. Also, we will investigate gamma oscillations are affected because MeCP2 is missing from one type of brain cell or synapse. We will also examine whether putting MecP2 back into certain neuron types can rescue gamma oscillations and cognitive deficits in mice that otherwise lack MeCP2. Together, these findings will demonstrate the role for MeCP2 in brain function and the mechanisms that contribute to cognitive deficits in Rett syndrome.

Rett syndrome is a devastating neurological disorder affecting females and is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Affected girls develop normally during the first 6 to 18 months of life but quickly regress, losing acquired language, motor and cognitive abilities. Previous work has demonstrated alterations in neuronal connectivity and synaptic communication in mouse models of RTT. However, few studies have focused on the consequences of these alterations at the network or behavioural levels. We have recently made the surprising discovery that loss of MeCP2 function impairs the generation of gamma oscillations and their coherence between regions. How MeCP2 regulates gamma oscillations and coordinates the function of synapses involved in its generation remains unclear. We hypothesise that cognitive deficits in Rett syndrome occur by disrupting inhibition-dependent synchronisation of neuronal activity leading to impairments in neuronal oscillations. In our first aim, we will characterise hippocampal gamma oscillations in mouse models of Rett syndrome in vitro and in vivo. In our second aim, we will define the cellular and synaptic mechanisms by which loss of MeCP2 perturbs gamma oscillations. In the third aim, will identify the causal role for specific interneuron classes in the breakdown of gamma oscillations. In this final aim, we will also examine whether activation of silenced Mecp2 allele in specific interneuron classes can rescue the function of gamma oscillations in mouse models of Rett syndrome. These aims will settle several fundamental questions about MeCP2's roles in regulating synaptic coordination, will yield important insights into the neural network mechanisms that lead to the manifestation of behavioural alterations, and could yield promising candidate therapies.

Societal impact: Contribution to our understanding of Rett syndrome (RTT).

RTT is a devastating neurological disorder that represents the second leading cause of intellectual disability in females, and for which there are no effective treatments or cures. Affected girls appear to develop normally during the first 6 to 18 months of life but quickly regress, losing acquired language and motor skills, seizures, and cognitive deficits. Patients survive up to the sixth or seventh decade of life in a severely debilitated physical condition representing a tremendous burden to the patients, their families and carers. RTT is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Despite the broad phenotypes, activation of a silenced Mecp2 allele in neurons reverses RTT-like phenotypes, even after their presentation. Thus RTT may be a curable disorder. However, without a mechanistic understanding of how MeCP2 affects brain function, the design of new therapeutics is not possible. We have established a framework to identify the causally important mechanisms by which loss of Mecp2 in mice leads to cognitive deficits at the neural network, cellular and molecular levels. Through this, we are then able to determine whether restoration of neuronal function at these different levels can ameliorate cognitive deficits in RTT.

Academic Impact: Understanding the role of MeCP2 in function of neural networks.

The neurobiological basis of RTT has been underscored by the observation that conditional deletion of Mecp2 from the brain recapitulates RTT-like phenotypes. At the molecular level, MeCP2 plays an important role in the repression of gene transcription, with a bias towards long genes and those involved in neuronal connectivity and communication. At the cellular level, despite no overt changes in intrinsic neuronal electrical properties, loss of MeCP2 leads to various cell type-dependent changes in synaptic function. Although recordings from single neurons can assess the function of MeCP2 at the cellular level, they do not have the ability to monitor how output representations of a network, or monitor how information transfer is coordinated across neuronal networks. Understanding how loss of MeCP2 affects the function of neural circuits at the local level and how it affects the communication between neural networks remains a significant challenge for the field. The proposed work will bride this divide and provide new and significant understanding of how MeCP2 controls brain function and consequently how its loss leads to behavioural abnormalities in Rett syndrome. In addition, by studying the contribution of individual interneuron types to neuronal oscillations will greater understand our understanding of these oscillations. Since all psychiatric disorders are associated with altered oscillations and these oscillations are readily translatable to humans, we expect their to be significant benefits to researchers in other fields of neuroscience and those who study disease.

Academic Impact: Training of Postdoctoral Research Associate and Undergraduates

This project will provide excellent training in state-of-the-art genetic and electrophysiological procedures that are applicable to an academic or industrial career. The training will be provided by myself, courses by the University of York Technology Facility. In addition, the PDRA will be encouraged to apply for supplemental internal or external funding (e.g. postdoctoral fellowships from MRC/International Rett Syndrome Foundation) to enhance their grant writing skills. The lab will host summer undergraduate research students to foster interest and skills relating to neuroscience. In 2015, I mentored a Wellcome Trust-funded undergraduate student who provided some of the pilot data in this application. The PDRA will be responsible for mentoring students to provide project and people management skills.