Transcriptomics has revealed that cortical inhibitory neurons exhibit a great diversity of fine molecular subtypes, but it is not known whether these subtypes have correspondingly diverse activity patterns in the living brain. We show that inhibitory subtypes in primary visual cortex (V1) have diverse correlates with brain state, but that this diversity is organized by a single factor: position along their main axis of transcriptomic variation. We combined in vivo 2-photon calcium imaging of mouse V1 with a novel transcriptomic method to identify mRNAs for 72 selected genes in ex vivo slices. We classified inhibitory neurons imaged in layers 1-3 into a three-level hierarchy of 5 Subclasses, 11 Types, and 35 Subtypes using previously-defined transcriptomic clusters. Responses to visual stimuli differed significantly only across Subclasses, suppressing cells in the Sncg Subclass while driving cells in the other Subclasses. Modulation by brain state differed at all hierarchical levels but could be largely predicted from the first transcriptomic principal component, which also predicted correlations with simultaneously recorded cells. Inhibitory Subtypes that fired more in resting, oscillatory brain states have less axon in layer 1, narrower spikes, lower input resistance and weaker adaptation as determined in vitro and express more inhibitory cholinergic receptors. Subtypes firing more during arousal had the opposite properties. Thus, a simple principle may largely explain how diverse inhibitory V1 Subtypes shape state-dependent cortical processing.

The symposium will start with Prof Song-Hai Shi who will present “Assembly of the neocortex”. Then, Dr Lynette Lim will talk about “Shared and Unique Developmental Trajectories of Cortical Inhibitory Neurons”. Dr Alfredo Molina will deal with the “Tuneable progenitor cells to build the cerebral cortex”, and Prof Tomasz Nowakowski will present “Charting the molecular 'protomap' of the human cerebral cortex using single cell genomic”.

Recent human gene discovery efforts show that gain-of-function (GOF) variants in the KCNT1gene, which encodes a Na+-activated K+ channel subunit, cause severe epilepsies and other neurodevelopmental disorders. Although the impact of these variants on the biophysical properties of the channels is well characterized, the mechanisms that link channel dysfunction to cellular and network hyperexcitability and human disease are unknown. Furthermore, precision therapies that correct channel biophysics in non-neuronal cells have had limited success in treating human disease, highlighting the need for a deeper understanding of how these variants affect neurons and networks. To address this gap, we developed a new mouse model with a pathogenic human variant knocked into the mouse Kcnt1gene. I will discuss our findings on the in vivo phenotypes of this mouse, focusing on our characterization of epileptiform neural activity using electrophysiology and widefield Ca++imaging. I will also talk about our investigations at the synaptic, cellular, and circuit levels, including the main finding that cortical inhibitory neurons in this model show a reduction in intrinsic excitability and action potential generation. Finally, I will discuss future directions to better understand the mechanisms underlying the cell-type specific effects, as well as the link between the cellular and network level effects of KCNT1 GOF.