Sensitive periods for interneuron development supporting cognitive flexibility

Cognitive flexibility is a core component of executive functioning that is impaired in a range of neuropsychiatric
disorders. The prefrontal cortex (PFC) supports cognitive flexibility in the adult, and alterations in prefrontal
function likely contribute to impairments in this cognitive process. Cognitive flexibility, like other aspects of
executive functioning, develops slowly across postnatal development. Developmental refinement of prefrontal
circuitry and function is theorized to underlie the protracted acquisition of cognitive abilities, and abnormalities in
this refinement may contribute to deficits in prefrontal circuitry and function in the context of psychiatric disorders.
While the early stages of prefrontal circuit development are largely governed by genetic programs, subsequent
circuit refinement is heavily dependent on activity. Postnatal maturation of GABAergic tone is poised to
powerfully regulate cortical activity—providing a source of excitability during the first postnatal week that rapidly
changes to inhibition thereafter. Importantly, developmental dysfunction of interneurons, especially those
expressing parvalbumin (PV) or somatostatin (SST), is linked with impaired set-shifting behavior and prefrontal
circuit function in adulthood. Yet, how activity in PV and SST interneurons influences prefrontal
circuit development—including the development of the interneurons themselves—during different developmental
time windows is a fundamental gap in our knowledge. Further, once mature connectivity is established, how SST
and PV interneurons work together to engage cortical activity to support cognitive flexibility in adulthood, remains
unknown.
We hypothesize that during early postnatal development, prefrontal SST activity is required for establishing
increasing thalamocortical drive onto PV cells that, in turn, sustains and augments the strength of the connections
these PV cells make onto pyramidal cells, and that PV activity subsequently iteratively refines the strength of
incoming excitatory drive from cortical and subcortical sources. This developmental maturation in activity
establishes proper connectivity of PV and SST interneurons in adulthood, whose activity is essential for mature
prefrontal network function supporting cognitive flexibility. To test this hypothesis, in Aim 1 we will examine how
PV and SST interneurons organize PFC network activity to support extra dimensional attentional set shifting in
adult mice. In Aim 2, we will test how inhibiting activity of prefrontal PV or SST interneurons during different
developmental windows using the DREADD receptor, hM4DGi, affects adult network function and behavior using
the physiological and behavioral outcomes assessed in Aim 1. Understanding how PV and SST interneurons
support cognition, and how developmental perturbations of these cells affect adult PFC function, will provide
insight into neurobiological origins of cognitive deficits in psychiatric disorders and more broadly into the role of
cell-type selective GABA release in sculpting the developing PFC.

Grant Number: 5R01MH128277-04
NIH Institute/Center: NIH
Principal Investigator: SARAH CANETTA