Roles of neuronal integrative mechanisms in olivo-cerebellar networks and motor behaviour

The brain is the most complex organ in the body. A vital function of the brain is to organize or integrate vast quantities of information into a coherent form that enables us to behave or act in certain ways and to respond to events appropriately. There is increasing evidence to suggest that common psychiatric disorders, such as schizophrenia and autism, involve failure of the brain to integrate information correctly. However, because of an absence of tools that selectively manipulate integration of neuronal activity, it has been difficult to study the roles of neuronal integrative mechanisms in normal behavior or in disease. This study builds on recent work in which I found that deletion in mice of the HCN1 gene, which encodes an ion channel important for neuronal integration, leads to subtle, but profound changes in behaviour. In particular, deletion of HCN1 ion channels impairs learning of coordinated movements, but enhances learning of complex spatial navigation problems. This work indicates that mice with deletion of the HCN1 gene may be an important model to study how neuronal integrative mechanisms influence learning and behavior. However, the specific mechanisms through which deletion of HCN1 channels modify behaviour are not yet clear. In the present study we will develop two new directions for investigation. First, we will determine how HCN1 channels influence integration by neurons in the inferior olive, a brain region important for motor behavior and implicated in brain disorders including autism. Second, we will ask how motor behavior is affected when genetic deletion of the HCN1 channel is restricted to another important class of neuron, the cerebellar Purkinje cell. Purkinje cells are the output neurons of the cerebellar cortex and their degeneration underlies many common forms of ataxia. This study will give new insights into the cellular mechanisms used for integration and encoding of information in the brain and will establish principles for investigating and understanding the roles of neuronal integrative mechanisms in disease. This could lead to a better understanding of the fundamental mechanisms of brain function and may suggest new therapeutic approaches for common psychiatric and neurological disorders.

A fundamental function of the brain is to integrate vast amounts of information into a coherent form that can be used to guide behaviour. Disruptions to higher order properties of the brain that involve precise integration of neuronal activity are increasingly recognized as possible disease mechanisms, particularly for complex psychiatric disorders such as schizophrenia and autism. At the cellular level, integration occurs continuously as neurones determine whether to generate an output in response to recently activated synaptic inputs. However, because of the absence of tools that selectively manipulate integration of neuronal activity, it has been difficult to study the roles of neuronal integrative mechanisms in normal behavior or in disease states. I recently adopted a new approach to this problem, using a combination of genetic, electrophysiological and behavioural methods to investigate the functions of the HCN1 channel, an ion channel important for integration of neuronal activity. I found that deletion of HCN1 channels impairs learning of coordinated movements, but enhances learning of complex spatial navigation problems (Cell, 2003, 115:551-64; Cell, 2004, 119:719-32), indicating that genetic modification of HCN1 channels may be a useful way to study how neuronal integrative mechanisms influence behavior. I now plan to build on this work as part of a long-term strategy to investigate the cellular mechanisms of behaviour using well-defined manipulations of neuronal properties. To address the roles of neuronal integrative mechanisms in behaviors that involve the inferior olive and cerebellum we will develop two new directions. (1) We will determine how HCN1 channels influence integration by neurones in the inferior olive. (2) We will ask how deletion of HCN1 channels restricted to cerebellar Purkinje cells influences motor behavior. To examine the biophysical effects of deleting HCN1 channels we will use patch-clamp recordings from neurones in mouse brain slices. We will focus on the contribution of HCN1 channels to hyperpolarization-activated membrane currents, to spontaneous sub-threshold neuronal activity and to integration of neuronal inputs. To examine the effects on motor behaviour of restricting deletion of HCN1 channels to cerebellar Purkinje cells we will use a range of previously described behavioral tests. These experiments will aim to establish principles for investigating and understanding how neuronal integrative mechanisms influence circuit function and behavior. They may also lead to new therapeutic approaches for common psychiatric and neurological disorders.