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 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. Our working hypothesis is that this is achieved through a two-step process, which we refer to as “Cardinal” and “Definitive” specification.
(Research Topic 1 - The Embryonic Specification of Interneurons). The first step in the specification of interneurons involves genetic programs that in accordance with their birthdate create a finite number of cardinal subtypes. The vast majority of forebrain GABAergic interneuron populations arise during embryogenesis from one of three transient progenitor zones, the medial, lateral and caudal ganglionic eminences (MGE, LGE, CGE, respectively). Recently, we have used high-throughput single cell RNA-seq methods to determine the transcriptional trajectories that mark the emergence of this diversity from these proliferative zones. To our great surprise, the characteristic clades that are so evident in the adult exhibit very similar transcriptomes until the first postnatal week. How can we reconcile this late appearance of transcriptional diversity with the strong evidence from my laboratory and others that interneuron subtypes relate to their anatomical origin and birthdate within the ganglionic eminences? At the single cell level, we have identified 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.
(Research Topic 2 - 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”. We hypothesize that following the tiling of these newly born cardinal subtypes across different brain structures, local cues act to create the definitive subtypes characteristic of each distinct cortical and subcortical area. 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.
(Research Topic 3 -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. A critical aspect of this effort is to use genetic and viral techniques to investigate the synaptic assembly and function of interneuron circuits. 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. Recent success in our laboratory in creating AAVs whose expression is engineered to be restricted to interneurons (Dimidschstein et al. 2016), has spurred us to initiate a broader effort to use similar methods to target particular interneuron subtypes. With such tools, a systematic effort to examine the function of different interneuron populations in both genetically and non-genetically tractable animal species can be attempted.
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