Homer and connectivity of brain circuits
What is the problem?
In Australia, it is suggested that 45% of the population will be affected by a mental health condition at some stage of their lives. Depression, epilepsy, addiction, schizophrenia, and autism spectrum disorders (ASD) all contribute to an immense economic burden and at the present time, there are few effective treatments. While our understanding of the underlying causes of these disorders is evolving, the complexity of the brain and related genetics has hindered the development of effective treatments. There is now sound experimental evidence to show that disruptions to normal connections between nerve cells, (neurons) drive most of these disorders. During the early development of the brain, neurons extend axons to connect, or synapse with target cells. The growing tip of the neuron, the growth cone, navigates towards the synaptic target in a process termed axon guidance, to form a synapse, or neuron-neuron connection (Fig.1). Brain development ultimately constructs billions of these synapses which are continually refined as we experience everyday activities and it is this process that is the fundamental building block of learning, memory formation, and cognition.
Figure 1
Identifying the cause
Significantly, proteins that regulate this process have been identified as risk factors in several neurodevelopmental disorders. For example, the Homer protein family is important for normal function (or homeostasis) at the synapse as well as in the growth cone during axon guidance and has been implicated in disorders such as depression and intellectual disability. Homer is therefore thought of as a protein that controls common signalling pathways on both sides of the synapse. A recently identified rare de novo human gene variant in the Homer1 gene (unpublished), where affected individuals suffer from epilepsy, intellectual disability, depression and some ASD-like symptoms, are being explored and investigated at length. We hypothesise that this Homer variant will perturb common signalling pathways at the synapse and growth cone, causing disruptions to normal brain connectivity.
How will we solve these questions?
Further research into specific de novo gene variants are required to elucidate how the Homer gene variant disrupts normal function in synapses and how basic nervous system development is impacted in living organisms. This has the exciting potential to translate basic science outcomes with the aim of developing novel therapeutic targets for a broader range of neurodevelopmental disorders.