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

Abstract

Local circuit GABAergic neurons, including parvalbumin (PV)-containing basket cells, likely play a key role in the development, physiology, and pathology of neocortical circuits. Regionally selective and well-defined decreases in PV have been described in human postmortem schizophrenic brain tissue in both the hippocampus and prefrontal cortex. Animal models of schizophreniform dysfunction following acute and/or chronic ketamine treatment have also demonstrated decreases in PV expression. Conflicting reports with respect to PV immunoreactivity following acute and chronic ketamine treatments in rodents question the utility of using PV as a biological marker of pathology-related dysfunction. The current literature lacks sufficient and systematic characterization of normative PV expression in pharmacologically and behaviorally naïve rodent tissue. In order to understand developmental changes in PV and its putative role in neuropathology, we examined the baseline distribution of the number of cells expressing this protein at distinct developmental ages. The present study examined PV cell counts across the septotemporal axis of the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus, as well as within the retrosplenial, somatosensory, and prefrontal cortices, in 1-, 6-, and 12-month-old naïve rats. Our findings suggest that the hippocampal PV+ cell number significantly decreases as a function of age with considerable regional (CA1, CA3, and DG) and septotemporal variation, a finding that was specific to the hippocampus. Additionally, we observed a modest increase in PV cell number within the prefrontal (anterior cingulate) cortex, which is in line with findings indicating a delayed developmental maturation of this region. The present work highlights decreases in PV+ cell counts within the hippocampus across development, and points to the need for a greater understanding of the role of PV and local circuit developmental changes, as well as consideration of their development when modeling developmentally related neuropathological disorders (e.g. schizophrenia, autism).

Parvalbumin Loss Following Chronic Sub-Anesthetic NMDA Antagonist Treatment is Age-Dependent in the Hippocampus: Implications for Modeling NMDA Hypofunction

“…The present work supports previous studies detailing a developmentally-dependent normative decrease in PV cell count within all sub-regions of the HPC (CA1, CA3, DG), but not within adjacent cortical regions in control rats (Honeycutt et al, 2016). Importantly, this work is the first to detail a novel dissociation between the effects of chronic KET administration on PV cell count based on age of treatment and anatomical region, without regard to time of tissue collection.…”

“…Findings indicating developmental changes in PV from young to adult rodents provide a compelling argument for considering age as a factor. Specifically, our group and others have presented evidence of decreased PV within the HPC in adult compared to young rodents (de Jong et al, 1996;Honeycutt et al, 2016). These findings indicate a distinct developmental trajectory of PV phenotype which likely influences the efficacy and/or outcomes of experimental treatments based on subject age.…”

“…Slides containing tissue processed for PV immunoreactivity were analyzed using a Nikon Eclipse E600 (Melville, NY) upright microscope equipped with an Insight SPOT digital camera (Diagnostic Instruments, Inc.). Photomicrographs of regions of interest including: retrosplenial Nomura et al, 1997 andHoneycutt et al, 2016), were catalogued and stored digitally for analysis by a researcher blind to treatment and age. For additional sampling and analysis parameters, see previously reported methods from our group (Honeycutt et al, 2016) and Figure1B for schematic of counting regions.…”

Glutamatergic drive along the septo-temporal axis of hippocampus boosts prelimbic oscillations in the neonatal mouse

“…It has been proposed that the differences in theta dynamics along the septo-temporal axis result from distinct innervation, on the one hand, and from specific intrinsic properties of hippocampal neurons, on the other hand. Cholinergic projections of different origin in the dHP and i/vHP ( Stewart and Fox, 1990 ; Amaral et al, 2007 ) as well as maturational differences in the intrinsic resonant properties of hippocampal neurons and notable gradients of parvalbumin immunoreactivity along the septo-temporal axis ( Honeycutt et al, 2016 ) may contribute to the observed differences.…”

Increased Dendritic Branching of and Reduced δ-GABAA Receptor Expression on Parvalbumin-Positive Interneurons Increase Inhibitory Currents and Reduce Synaptic Plasticity at Puberty in Female Mouse CA1 Hippocampus

“…The increase in dendritic branching of PV+ interneurons at puberty could result in increased inhibitory synaptic input to the pyramidal cells and may underlie the observed increase in phasic current at puberty, although other possibilities such as presynaptic effects and altered PV+ activity, as discussed below, may play a role. Increases in PV expression have been reported in the hippocampus across development (Wu et al, 2014) unaccompanied by increases in interneuron numbers (Honeycutt et al, 2016), although puberty has not been investigated until the present study. Our results showing an increase in dendritic branching at puberty may underlie these findings.…”