Summary: Researchers clarify changes in cortical neural circuits that may underlie disrupted neurodevelopment and cognitive impairments in schizophrenia.
Source: Elsevier
New insights into GABAergic microcircuit alterations in schizophrenia
Researchers at the University of Pittsburgh report detailed postmortem findings that refine our understanding of how cortical GABAergic microcircuits are altered in schizophrenia. Published in Biological Psychiatry, the study led by Dr. Kenneth Fish examines specific inhibitory interneurons called chandelier cells and their specialized synaptic arrays—known as cartridges—that regulate pyramidal neuron output in the prefrontal cortex. The results point toward selective, layer-specific changes consistent with atypical neurodevelopment rather than a uniform loss of inhibitory signaling.
Earlier postmortem work, including studies from Professor David Lewis’s laboratory, suggested widespread deficits in GABAergic signaling in schizophrenia, based on reduced markers of GABA reuptake across multiple cortical layers. Chandelier cells provide powerful, targeted inhibition at the axon initial segment of pyramidal neurons, using the inhibitory transmitter GABA and forming cartridges composed of multiple presynaptic boutons. Those prior findings were interpreted as evidence for broadly reduced GABA-mediated inhibition and compensatory changes at postsynaptic sites.
However, the new University of Pittsburgh study provides a higher-resolution view by comparing protein markers involved in GABA synthesis and packaging and by distinguishing transcriptionally defined subtypes of chandelier cell cartridges. The team examined prefrontal cortex tissue from 20 individuals with schizophrenia and 20 matched comparison subjects, quantifying the density and molecular composition of chandelier cell cartridges across cortical layers.
Key findings: a selective increase in a chandelier cell subtype
Contrary to the idea of a universal GABA deficit, the study found that markers of GABA synthesis (GAD67) and vesicular GABA transport (vGAT) per bouton were not reduced in schizophrenia. Instead, the most striking change was a nearly threefold increase in the density of cartridges belonging to a transcriptionally unique subset of chandelier cells that express calbindin (CB+) — and this increase was restricted to layer 2 of the prefrontal cortex.
The CB+ chandelier cell subset represents a small fraction of chandelier cells in the prefrontal cortex. Cartridges that lack calbindin (vGAT+/CB–) did not differ in density between schizophrenia and comparison groups, nor were there changes in cartridge density in cortical layers 3–6. Additionally, protein levels of vGAT, CB, and GAD67 per bouton, and the number of boutons per cartridge, were comparable between groups.
Interpretation: developmental pruning and layer specificity
The layer-specific increase in CB+ cartridge density suggests a developmental origin. Chandelier cell cartridges normally undergo substantial pruning during brain maturation; layer 2 of the cortex matures later than deeper layers. The selective enrichment of CB+ cartridges in layer 2 in schizophrenia implies that normal pruning of these particular cartridges may be blunted, yielding an elevated local density rather than a deficit in GABA synthetic capacity.
These findings refine previous models by showing that GABA synthesis and packaging at chandelier boutons are preserved, while the organization and density of a specific chandelier cell subclass are altered. This shifts attention toward cell-type-specific developmental mechanisms and circuit remodeling in the prefrontal cortex as contributors to the cognitive symptoms of schizophrenia.
Implications for research and treatment
According to Kenneth Fish, identifying transcriptionally distinct subtypes of human brain cells is essential for understanding both normal brain function and disease. The results underscore the importance of studying defined cell populations in psychiatric disorders. By pinpointing selective developmental disruptions in specific inhibitory microcircuits, this research could guide more targeted strategies to treat, prevent, or mitigate circuit-level dysfunction in schizophrenia.
Source: Rhiannon Bugno, Elsevier
Image source: NeuroscienceNews.com image is in the public domain.
Original research: “Alterations in a Unique Class of Cortical Chandelier Cell Axon Cartridges in Schizophrenia” by Brad R. Rocco, Adam M. DeDionisio, David A. Lewis, and Kenneth N. Fish. Biological Psychiatry, published online June 2017. doi:10.1016/j.biopsych.2016.09.018
Abstract (paraphrased)
The axons of chandelier cells form cartridges of boutons that innervate the axon initial segment of pyramidal neurons. Prior work detected lower cartridge density using GABA transporter immunoreactivity and higher densities of GABAA receptor α2 subunit at axon initial segments in superficial prefrontal cortex layers, interpreted as compensatory responses to reduced GABA. In this study, cartridges immunoreactive for vesicular GABA transporter (vGAT) and the subset containing calbindin (CB) were quantified in prefrontal cortex tissue from 20 matched schizophrenia and comparison pairs.
Results showed a 2.7-fold higher mean density of vGAT+/CB+ cartridges exclusively in layer 2 of schizophrenia subjects, while vGAT+/CB– cartridge density was unchanged. Protein levels of vGAT, CB, and GAD67 per bouton and the number of boutons per cartridge did not differ between groups. These findings support the idea that normal developmental pruning of CB+ chandelier cell cartridges in layer 2 may be blunted in schizophrenia.
Alterations in a Unique Class of Cortical Chandelier Cell Axon Cartridges in Schizophrenia — Brad R. Rocco, Adam M. DeDionisio, David A. Lewis, Kenneth N. Fish. Biological Psychiatry, June 2017. doi:10.1016/j.biopsych.2016.09.018