Axonal myelination of interneurons in cortex: functional significance and plasticity

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ABSTRACT Parvalbumin-containing (PV+) fast spiking basket cells comprise an important subset of interneurons in the brain. Cortical PV+ basket cells regulate the activity of principal pyramidal neurons and other interneurons to influence a variety of behaviors. Diminished PV+ activity in cortex is associated with numerous psychiatric disorders, including schizophrenia and other dissociative disorders, and autism. We propose to investigate the properties of PV+ interneurons and their influence on their postsynaptic targets by focusing on the smallest element of a neural circuit, the synaptic connection between two single neurons. We will apply a multipronged approach by combining electrophysiological recordings from two synaptically connected neurons, with single cell transcriptomic analysis of both neurons and high-resolution array tomographic reconstruction of the anatomy of their synaptic connectivity. In these studies, the presynaptic neuron will be a PV+ basket cell, with the postsynaptic partner being a pyramidal neuron or another interneuron. We propose three specific aims to study the function and structure of the axon-myelin unit of PV+ interneurons within this quantal element of the neural circuitry. 1) We will elucidate the rules of PV+ interneuron connectivity in the adult neocortex by comparing the physiological and anatomical properties of the synaptic connections between individual neurons (PV+ presynaptic), including synaptic strength, latency, and failure rate, the directionality of activity- induced plasticity, as well as the number of synapses created between the two neurons, the number of connecting axon paths, length and thickness of axon paths and the extent of axon myelination. 2) We will characterize the synapses that PV+ basket cells project onto different compartments of the postsynaptic neuron, and specifically the much less understood PV+ synapses onto distal dendrites and spines, including their axonal paths and synaptic molecular content, comparing those to soma-directed synapses. In the case of spine synapses we will also clarify the identity of the excitatory synapse onto the same spine. 3) We will study the gene expression in PV+ interneurons and in their postsynaptic target neurons with single cell RNA-seq, and correlate gene expression patterns with the electrophysiological properties of synaptic transmission and synaptic plasticity, and with the morphological characteristics of these synaptic connections revealed by 3D reconstruction by array tomography, including, but not limited to myelination, axonal path length, number of synapses, and their molecular character. By elucidating the function of PV+ cells and their myelinated axon in the smallest neural circuit interaction, we aim to gain insight into how these crucial elements of brain circuits contribute to normal and pathological brain function, thus providing the knowledge base needed for improved treatment design for PV+ interneuron-related disorders.