Can learning deficits in neurodevelopmental disorders be reversed by restoring gene function in the adult brain?

Approximately 1-2% of the UK population, 1.5 million individuals, suffer from intellectual disability, defined as a non-verbal IQ below 70. Almost half of these individuals also suffer from additional mental health problems. Intellectual disability severely affects the ability of individuals to function independently in society, placing a huge strain on families, carers and the healthcare system.

We now know that 25% of intellectual disabilities have a genetic cause. It is widely assumed that the majority of these intellectual disabilities are caused by problems during brain development in the womb or shortly after birth and that these brain abnormalities are essentially irreversible. However, it remains possible that the genes responsible for the learning difficulties in these individuals have direct roles during learning and memory and that we may be able to correct, treat or ameliorate some of these learning difficulties, thereby significantly improving the quality of life for these individuals.

The entrenched notion of the irreversibility of developmental brain disorders has been challenged by paradigm-shifting experiments in mice. Adrian Bird's group has shown that a severe, progressive developmental brain disorder that eventually result in death, Rett syndrome, can be reversed by restoring gene function in mice, even in adults already showing symptoms. These important findings raise the possibility that some of these disorders might be treatable by interventions after birth and even in adulthood. However, apart from Rett syndrome, we have little direct evidence that this is the case for other conditions. The focus of this pilot grant is to test this idea for a number of other genetic brain disorders associated with intellectual disability.

We propose to determine if the genes associated with four different genetic conditions associated with intellectual disability have direct functions in learning and memory and if restoring normal gene function in mutant mouse models can reverse learning deficits. We will perform two different sets of experiments: 1) we will inactivate genes in brain cells (neurons) after they have formed in the developing brain, or in neurons in the adult brain, to determine if they function directly in learning and memory and 2) we will test if restoring gene function in neurons in adult mice with mutations in these genes can reverse deficits in learning and memory.

This is a pilot project specifically focused on these two critical experiments. Brain development and disease is complex and many important questions remain to be answered. For instance, it will be of fundamental importance to eventually understand exactly how mutations in these genes cause intellectual disability in these patients. These genes most likely control many different processes, including those that operate during brain development and those responsible for the formation, storage and recall of memories. Rather than studying all these different processes, it is important that we first test if these genes function directly in learning and memory and if learning deficits are reversable. This measured approach will allow us to focus future efforts on the most relevant developmental time points, cell types and processes. If we find evidence that these genes function in adult neurons and that we can rescue learning deficits in adults, our future work will focus specifically on understanding how these genes function in adult neurons.

This project aims to determine if genes mutated in individuals with intellectual disability have direct roles in learning and memory and if learning deficits can be reversed by restoring gene function in the adult brain. >1.5 million people in the UK suffer from intellectual disability. It is widely assumed that these conditions are caused by abnormal brain development, and therefore irreversible. However, this may not be so. A substantial proportion of genes associated with intellectual disability encode chromatin regulators. These factors function at the level of the epigenome, and therefore control processes that are reversible. Thus, if we can identify which of these genes control the processes necessary for learning and memory, and determine to what extent learning deficits can be ameliorated by restoring gene function, we can envisage the development of targeted treatments for these conditions.

This project will focus on four of these chromatin regulators and will answer two critical questions. Do these genes directly control processes necessary for learning in post-mitotic neurons? Can restoring the functions of these genes in neurons in the adult brain rescue learning and memory deficits?

First, we will delete genes either in newborn, excitatory neurons of the embryonic neocortex and hippocampus, or mature excitatory neurons of the hippocampus only. Where these approaches are not possible due to the lack of an appropriate conditional mouse line, we will knock down gene expression in all cell types of the hippocampus. The effects on hippocampus-dependent learning will be assessed. Next, we will establish mutants that model the human conditions and restore gene expression in mature, excitatory neurons of the hippocampus to test if we can reverse learning deficits.

These experiments are critical to guide future research on the molecular and cellular mechanisms of learning, with the aim of developing approaches to restore cognitive function.