2014-15 MPFI Seminar Series
Fundamental to understanding brain function is gaining an appreciation of how the it is assembled. Inhibitory interneurons display a remarkable degree of heterogeneity and play an integral role in shaping the flow of information through all brain areas. Work from my laboratory over the past decade has sought to understand both how interneuron diversity is generated and how various interneuron subtypes become precisely embedded in the broad swath of circuits in which they are required. We have proposed a working model of how this is achieved that involves a initial step where “Cardinal” classes of interneurons are genetically specified into a relatively small number of subtypes, each of which represent interneurons that possess similar intrinsic properties, morphologies and propensities as to both the cell types (excitatory or inhibitory) and cellular compartments (dendritic, somal or axonal) that they innervate. Cardinal specification, which we posit is determined upon interneurons become postmitotic, is followed by “Definitive” specification. This second step we believe occurs post-migration when interneurons have attained their final position within the brain and is characterized by local cues including activity and trophic signals impinging on immature neurons to determine their appropriate and precise afferent and efferent connectivity within given brain regions. In this presentation, I will discuss recent work from my laboratory that supports this model. In the first portion of my talk, I will present lineage data indicating that specific lineages give rise to interneurons that population broad structures within the telencephalon and are both spatially dispersed and unrestricted by functional boundaries between areas as discrete as the cortex, the hippocampus and the striatum. I will then focus on a particular early born population of interneurons, the Layer 5/6 Martinotti neurons that are generated at E10.5. In investigating their integration within the cortex we find that both the strength and number of their afferents and efferents change dynamically over development. Further, upon disruption of the early Martinotti interneurons network, the synaptic maturation of thalamocortical inputs onto parvalbumin interneurons is arrested. These results suggest that Martinotti interneurons function as a pioneer population whose transient early synaptic connectivity is essential for the establishment of thalamic recruitment of feed-forward inhibition mediated by parvalbumin interneurons.