Differential regulation of parvalbumin and calretinin interneurons in the prefrontal cortex during adolescence

Abstract

Determining the normal developmental trajectory of individual GABAergic components in the prefrontal cortex (PFC) during the adolescent transition period is critical because local GABAergic interneurons are thought to play an important role in the functional maturation of cognitive control that occurs in this developmental window. Based on the expression of calcium-binding proteins, 3 distinctive subtypes of interneurons have been identified in the PFC: parvalbumin (PV)-, calretinin (CR)-, and calbindin (CB)-positive cells. Using biochemical and histochemical measures, we found that the protein level of PV is lowest in juveniles (postnatal day -PD- 25–35) and increases during adolescence (PD45–55) to levels similar to those observed in adulthood (PD65–75). In contrast, the protein expression of CR is reduced in adults compared to juvenile and adolescent animals, whereas CB levels remain mostly unchanged across the developmental window studied here. Semi-quantitative immunostaining analyses revealed that the periadolescent upregulation of PV and the loss of the CR signal appear to be attributable to changes in PV- and CR-positive innervation, which are dissociable from the trajectory of PV- and CR-positive cell number. At the synaptic level, our electrophysiological data revealed that a developmental facilitation of spontaneous glutamatergic synaptic inputs onto PV-positive/fast-spiking interneurons parallels the increase in prefrontal PV signal during the periadolescent transition. In contrast, no age-dependent changes in glutamatergic transmission were observed in PV-negative/non fast-spiking interneurons. Together, these findings emphasize that GABAergic inhibitory interneurons in the PFC undergo a dynamic, cell-type specific remodeling during adolescence and provide a developmental framework for understanding alterations in GABAergic circuits that occur in psychiatric disorders.

Developmental Age Differentially Mediates the Calcium-Binding Protein Parvalbumin in the Rat: Evidence for a Selective Decrease in Hippocampal Parvalbumin Cell Counts

“…This pattern of HPC septotemporal PV gradient was selective to CA1 and DG regions, with CA3 regions showing a more consistent pattern of PV expression across the long axis in all age groups. Thus, our data support a growing body of evidence describing age-related variation in the expression of PV across the rat life span [[48], [58,59,60]; for a review, see [49]]. Such findings are also consistent with studies reporting age-related decreases in PV expression within the HPC [61,62,63,64].…”

“…Additionally, PV likely varies within that multimonth window across the three main HPC subregions, and likely exhibits variation within these across the septotemporal axis. Evidence of this dynamic expression has been shown by Caballero et al [59], reporting that ventral HPC subregions exhibit increases in PV+ neurons up to P65-75 (roughly 2 months of age) in a pattern similar to prefrontal cortical areas [59,60]. With the exception of the cingulate cortex, the present work provides evidence for the stable expression of PV regardless of age within many neocortical areas (e.g.…”

“…The observation of a trend toward an increase in PV neuron count within the cingulate cortex (table 1; fig. 3) is consistent with both rat [60] and human [67,68] data, suggesting an increase in PV commensurate with age which likely underlies typical age-dependent, and therefore delayed, maturation of prefrontal inhibitory circuitry [65]. Such findings highlight the need for more thorough descriptions of PV+ neurons and, more generally, areal variation in local circuits across the neocortex where many areas exhibit developmental changes within the first weeks and month of age (in rodents), while others exhibit developmental changes over several months.…”

Effects of amphetamine exposure during adolescence on behavior and prelimbic cortex neuron activity in adulthood

“…Studies in non-human primates and rodents have revealed that normal PFC development involves significant increases in GABAergic function, including an increase in the expression and excitability of fast-spiking, parvalbumin-positive GABAergic interneurons (Caballero et al, 2014), an increase in spontaneous inhibitory postsynaptic currents in the pyramidal cells on which these interneurons synapse (Hashimoto et al, 2009;Cass et al, 2014), and changes in the subunit composition of GABAA receptors that would facilitate inhibitory transmission (Datta et al, 2015). In addition, dopaminergic control of inhibitory signaling in the PFC changes significantly during adolescence.…”

Evaluating long-term consequences of adolescent antipsychotic exposure

“…Recently, adolescent maturation of gamma-amino butyric acid (GABA)-secreting interneurons of the PFC has also been reported (Caballero et al 2014). A recent longitudinal magnetic resonance imaging (MRI) study in rats has also identified a peak in cortical thickness during adolescence and a continued increase in volume of cerebral cortex and striatum and myelination from adolescence to adulthood (until PND60) (Mengler et al 2014).…”