Associate Professor
Child Study Center
& Section of Neurobiology
230 South Frontage Road
New Haven CT
USA 06520
SHM, I-373

Introduction

In the Child Study Center’s Developmental Neurobiology Laboratory we study how genetic/environmental perturbations at critical stages in development cause aberrant differentiation of excitatory or inhibitory neurons, leading to altered ratios of brain excitation/inhibition and permanent repercussions on cognitive and motor behavior. An excitatory/inhibitory imbalance in specific forebrain systems due to disparate etiologies can underlie the pathogenesis of childhood neuropsychiatric disorders such as Tourette’s syndrome, ADHD, schizophrenia and autism.

tamoxifen-induced Cre recombinase activity as visualized by the beta-galactosidase reporter in the postnatal mouse brain Enlarge image

To study how neural stem cells respond to genetic and environmental factors over time, we developed a mouse model, the GFAPCreERT2 (GCE) line, which targets an inducible Cre recombinase to GFAP+ neural stem cells in vivo (Ganat et al, 2006)

Using this system we can:

cortical astrocyte generated from GFAP+ neural stem cell marked with a heritable EGFP reporter at postnatal day 5 Enlarge image

Rip+ cortical oligodendrocytes generated from GFAP+ stem cell marked with beta-gal reporter gene at postnatal day 5 Enlarge image

Cortical inhibitory interneuron generated from GFAP+ neural stem cells marked with a heritable betagal reporter gene at postnatal day 5 Enlarge image

1. mark neural stem cells at any given time and visualize their daughters
2. activate or inactivate genes controlling growth and differentiation in stem cells at any stage in development.

These mice will be crucial to investigate the molecular mechanisms and signaling systems that govern neural stem cell proliferation, differentiation and survival at both prenatal and postnatal stages of development, and how these systems react to both adverse and favorable events.

Mouse models cannot reproduce the complexity of the human brain and its functions. A central focus of our program is the direct investigation of excitatory and inhibitory neurons in the postmortem human brain using unbiased stereological sampling procedures. We were recently able to show that individuals with Tourette’s syndrome have a decrease in striatal parvalbumin (Kalanithi et al, 2005), but not other classes of striatal neurons. These interneurons comprise less than 2% of the total number of striatal neurons, yet they control and pattern the strength of thalamo-striatal and cortico-striatal inputs. These investigations have the potential to unveil the cellular mechanisms of tics and hyperactivity in these patients, the first step in creating better treatments.