Alterations in a Unique Class of Cortical Chandelier Cell Axon Cartridges in Schizophrenia

Abstract

Background The axons of chandelier cells (ChCs) target the axon initial segment (AIS) of pyramidal neurons, forming an array of boutons termed a cartridge. In schizophrenia, the density of cartridges detectable by GABA membrane transporter-1 (GAT1) immunoreactivity is lower, whereas the density of AISs detectable by immunoreactivity for the α2 subunit of the GABA-A receptor is higher in layers 2-superficial 3 of the prefrontal cortex (PFC). These findings were interpreted as compensatory responses to lower GABA levels in ChCs. However, we recently found that in schizophrenia ChC cartridge boutons contain normal levels of the 67 kDa isoform of glutamic acid decarboxylase (GAD67) protein, the enzyme responsible for GABA synthesis in these boutons. To understand these findings we quantified the densities of ChC cartridges immunoreactive for vesicular GABA transporter (vGAT+), which is present in all cartridge boutons, and the subset of cartridges that contain calbindin (CB+). Methods PFC tissue sections from 20 matched pairs of schizophrenia and unaffected comparison subjects were immunolabeled for vGAT, GAD67, and CB. Results The mean density of vGAT+/CB+ cartridges was 2.7-fold higher, exclusively in layer 2 of schizophrenia subjects, whereas the density of vGAT+/CB− cartridges did not differ between subject groups. Neither vGAT, CB, or GAD67 protein levels per ChC bouton, nor the number of boutons per cartridge, differed between subject groups. Conclusions Our findings of a greater density of CB+ ChC cartridges in PFC layer 2 from schizophrenia subjects suggests that the normal developmental pruning of these cartridges is blunted in the illness.

Axo-axonic Innervation of Neocortical Pyramidal Neurons by GABAergic Chandelier Cells Requires AnkyrinG-Associated L1CAM

“…The striking selectivity of ChC innervation at the AIS of PyNs has intrigued neuroscientists ever since the initial discovery of ChCs in the 1970s (Jones, 1975;Somogyi, 1977;Szentá gothai and Arbib, 1974). This interest has heightened with accruing evidence showing that this unique form of subcellular innervation allows ChCs to exert powerful yet precise control over cortical PyN spiking and population output (Howard et al, 2005;Inan and Anderson, 2014;Lu et al, 2017) and, in particular, given increasing reports linking ChC connectivity defects to neurological conditions, such as schizophrenia and epilepsy (Ariza et al, 2018;Del Pino et al, 2013;Lewis, 2011;Ribak, 1985;Rocco et al, 2017). Despite these findings, little to nothing is known about the mechanisms underlying the subcellular innervation of neocortical PyN AISs by ChCs.…”

“…In line with this, recent studies have shown a critical role for ChCs in the synchronization of firing patterns of large populations of PyNs in different functional states (Glickfeld et al, 2009;Lu et al, 2017;Viney et al, 2013;Woodruff et al, 2011;Zhu et al, 2004). The importance of proper ChC function is further underscored by the association of ChC connectivity defects with brain disorders such as schizophrenia, epilepsy, and autism spectrum disorder (Ariza et al, 2018;Del Pino et al, 2013;Lewis, 2011;Ribak, 1985;Rocco et al, 2017). To date, however, the molecular mechanisms governing neocortical ChC/PyN AIS innervation remain entirely unknown.…”

Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner

“…Based on translation of brain development milestones, the early time point of induction (E9.5) overlaps with the first trimester of human pregnancy [47] as well as with the onset of neurogenesis of cortical GABAergic interneurons [85]. Given the significant evidence for impairment of cortical GABAergic interneurons in human postmortem brain studies of patients with mental illness [86][87][88], the dysfunction of developmental programs for GABAergic interneurons might have causative effect on cognitive phenotype of the patients. Further studies of GABAergic circuitry development in environmental and genetic mouse models mimicking human developmental insults will reveal commonalities and differences in the affected subtypes of GABAergic interneurons across all developmental processes.…”

Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner

“…Based on translation of brain development milestones, the early timepoint of induction (E9.5) overlaps with the first trimester of human pregnancy 47 as well as with the onset of neurogenesis of cortical GABAergic interneurons86 . Given the significant evidence for impairment of cortical GABAergic interneurons in human postmortem brain studies of patients with mental illness[87][88][89] , the dysfunction of developmental programs for GABAergic interneurons might have causative effect on cognitive phenotype of the patients. Further studies of GABAergic circuitry development in environmental and genetic mouse models mimicking human developmental insults will reveal commonalities and differences in the affected subtypes of GABAergic interneurons across all developmental processes.…”