In mammalian neocortex, GABAergic interneurons consist of diverse cell types which regulate the balance and functional organization of neural circuitry. However, the developmental assembly of distinct GABA cell types into inhibitory circuitry remains poorly understood. For example, the chandelier cells (ChCs) specifically innervate pyramidal neurons (PyNs) at their axon initial segment (AIS), the site of action potential initiation, and defines a highly stereotyped circuit module. ChCs are specified at late embryonic gestation and are deployed to specific cortical layers through long range migration. However, it remains unknown how, upon reaching the cortex, the density and distribution of ChCs are regulated as a first step toward establishing their circuit connectivity. We have established an experimental system to track the developmental trajectory of ChCs, including their cortical circuit integration. Here I will study the developmental and activity-regulated mechanisms that guide the proper distribution of ChCs in the visual cortex, specifically at the border region between primary (V1) and higher (V2) visual areas. I have found that the density of layer 2 (L2) ChCs in mature cortex is reduced by half at V1/V2 border compared with neighboring V1 and V2 proper. During postnatal period, upon reaching L2 by postnatal day 7 (P7), ChCs are evenly distributed across V1 and V2, but then undergo massive apoptosis between P7-P14, with significantly more enhanced cell death at border region. I showed that this specific increase of cell pruning is regulated by axons and activity of callosal projection neurons (CPNs) in the contralateral cortex. Importantly, I found that retinal activity before eye opening regulates the density of ChCs at contralateral V1/V2 border. I hypothesize that the density and circuit integration of ChCs at V1/V2 border are regulated by trans-hemispheric callosal neuron inputs shaped by early postnatal retinal activity. I propose to first determine the functional long-range input from CPNs to ChCs during the period of ChC circuit integration, and investigate the role of CPN input in regulating the survival of ChCs at the V1/V2 border. I will then examine how an increase of ChC density at V1/V2 border impacts the interhemispheric synchronization of visual response properties, thought to be mediated by CPNs. Lastly, I will examine the role of correlated retinal activity in regulating ChC distribution, and importantly, establish the link between how retinal activity regulates ChC survival through CPN activity pattern. These studies will represent the first demonstration of how the assembly of a powerful inhibitory module is regulated by peripheral activity pattern through pyramidal inputs. This will shed light on understanding cortical circuit assembly as well as on mechanisms of aberrant circuit wiring underlying neurodevelopmental disorders.
Epilepsy frequently is associated with a variety of brain lesions, tumours or other structural abnormalities, which mostly affect the cerebral cortex. The chandelier cell, which is considered to be the most powerful cortical inhibitory neuron, is altered human temporal lobe epilepsy. Investigating the circuit integration of chandelier cells will shed light into the pathogenic mechanisms of neurological disorders such as epilepsy and suggest new strategies for therapy.
