Learning, behavior, and cognition, are ultimately an emergent property of the dynamic interactions of millions of neurons embedded within complex networks. Similarly, pathological brain states, such as mental retardation and autism, are ultimately expressed as a result of abnormal network function. The cognitive deficits that characterize some neurological diseases may not be caused by isolated molecular or cellular abnormalities, but rather from the effects of multiple interacting molecular and cellular abnormalities on network function. Indeed, the complexity and diversity of the neural and behavioral phenotypes associated with some diseases, have led to the suggestion that mental retardation and autism should also be studied from the perspective of abnormal network function. However, despite significant advances towards understanding the molecular, synaptic, and cellular mechanisms of neuronal function, as well as towards identifying the anatomical and systems level abnormalities associated with diseases, relatively little progress has been made in bridging these levels of analysis. That is, relatively little is known about how normal or abnormal behavior, learning, and cognition emerge from the interaction of neurons embedded in complex networks. The research described here is aimed at bridging this gap by studying the abnormal network properties in mice lacking the gene that causes Fragile X syndrome. The overarching hypothesis is that in Fragile X syndrome there is a deficit in the ability to coordinate the many different cellular and synaptic properties that govern network dynamics. We will extend preliminary findings on network abnormalities in cortical circuits from Fmr1-/- mice, and determine if the network dynamics is appropriately regulated in response to chronic patterned activity. Additionally, we will determine if a form of in vitro 'learning'is altered in cortical crcuits from the mouse model of FXS. If we confirm that deficits in in vitro 'learning'are present in isolated cortical networks from Fmr1-/- mice we will provide an important link between cortical circuit function and cognitive abnormalities. Furthermore, establishing deficits in what can be considered a form of in vitro learning, offers a strategy for rational therapeutic approaches for treatment.
Some neurological diseases-including mental retardation and autism-may not arise simply from isolated abnormalities at the molecular or cellular level, but from how multiple interacting factors at the molecular level alter processing at the level of networks of neurons. The current project is aimed at understanding network level abnormalities in what is among the most common causes of mental retardation and autism, Fragile X syndrome. Understanding the network abnormalities that are causally related to cognitive deficits will provide a strategy for rational therapeutic approaches for treatment.