Gordon Fishell, PhD

My laboratory is focused on three related questions:  How is the enormous diversity of local GABAergic inhibitory neurons within the cerebral cortex created? How do each of the unique interneuron subtypes become seamlessly integrated into the brain during development?  How does this diversity contribute to canonical excitatory/inhibitory circuits that ultimately shape mammalian brain activity? A century ago Ramon y Cajal dubbed these inhibitory interneurons,“the butterflies of the soul.” With characteristic insight, he inferred that these populations, which possess such enormous morphological diversity, would ultimately prove to have an equally impressive breadth of functional attributes. Recent studies have borne out this prediction and shown that inhibitory interneurons are much more than simple gatekeepers of excitation. Depending on which interneuron subtype is recruited, they are able to refine or unite brain activity in a startling multitude of ways.

Understanding how this wealth of cellular diversity is generated during development remains one of the most daunting problems in biology. In particular, we wish to understand not only how the vast variety ofinhibitory interneuron subtypes are generated but how they subsequently integrate into the bewildering array of neural circuits that are embedded in different brain structures. Our working hypothesis is that this is achieved through a two-step process, which we refer to as “Cardinal” and “Definitive” specification.

The Embryonic Specification of Interneurons. We have identified at the single cell level relatively small cohorts of genes expressed within the ganglionic eminences that we believe initiate the process of GABAergic neuronal diversification.  These genes encode for a combination of transcription factors and epigenetic regulators that we believe “seed” the cardinal identity of the interneuron subtypes that will subsequently appear later in development.  A present goal of the laboratory is to understand how these factors contribute to the specification of particular interneuron subtypes.

Interneuron Integration and Synapse Formation.  Interneuron diversity appears to only become fully determined after cells have migrated to their final settling positions within the brain. We have discovered strong evidence that local activity-dependent signaling results in the regional and layer-specific specification of interneurons upon completing migration.  We have dubbed this second phase of interneuron development “Definitive specification”. Recent work from our laboratory indicates that this process depends on excitatory to transcriptional coupling, which is linked through calcium-dependent signaling pathways. In addition, we have discovered that this also involves activity-dependent alternative splicing that occurs in a subtype specific manner. Understanding how different interneuronal subtypes initiate specific transcriptional programs and generate unique mRNA splice variants in response to activity is a central aspect of our present efforts.

Interneuron Function and Dysfunction.  As we have explored the molecular mechanisms by which interneurons becoming integrated into neural circuits, it has become clear that perturbation of this process can result in a variety of brain dysfunctions including autism spectrum disorder (ASD), intellectual disability (ID) and schizophrenia. A new and growing interest in the laboratory is therefore aimed at seeing if better understanding of these developmental events can lead to the development of new treatments for these disorders. To this end we are developing methods in a variety of mammalian species ranging from mice to non-human primates to query both the dynamics of circuit assembly and firing activity of specific interneuronal subtypes.  Our hope is to both understand the normal sequence of events leading to the formation of canonical brain circuits and to complement this with functional studies where these circuits are perturbed.

"...we wish to understand not only how the vast variety of inhibitory interneuron subtypes are generated but how they subsequently integrate into the bewildering array of neural circuits that are embedded in different brain structures."