Project 4

22q11 Vulnerability Genes and Cortical Interneuron Development

Description

Principal Investigator: Anthony LaMantia, PhD

Two hypotheses dominate current schizophrenia research: 1st, pathogenesis begins as early as the first trimester, and 2nd, the disease ultimately compromises cortical GABAergic interneurons. Nevertheless, it is not known whether interneuron integrity is compromised during early development in individuals at risk for schizophrenia. We will determine if heterozygous chr.22q11 deletion—VCFS/DiGeorge Syndrome,a major risk for schizophrenia—compromises interneuron proliferation, migration or differentiation. During early gestation, the progeny of basal forebrain GABAergic precursors migrate to forebrain regions including the neocortex and olfactory bulb—established sites of pathogenic change in schizophrenia. We hypothesize that diminished 22q11 gene expression compromises proliferation, migration, and placement of GABAergic interneurons leading to altered integration and maintenance in mature cortical circuits.

Specific Aim 1.  Does 22q11 deletion compromise the integrity of forebrain GABAergic precursors?

Rationale: Changes in precursor cell cycle can result in altered migration or differentiation. Preliminary evidence suggests that the cell cycle of cortical precursors is disrupted in mouse embryos with a chromosomal deletion parallel to 22q11DS. Accordingly, we will determine whether cell cycle timing as well as other proliferative characteristics of GABAergic precursors from the medial and lateral ganglionic eminences are compromised in deleted mice. We expect that at least S phase will be altered. Such changes might lead to altered competence for migration or differentiation.

Specific Aim 2.  Does 22q11 deletion compromise migration of GABAergic interneurons?

Rationale: Our preliminary evidence suggests that 22q11 deletion disrupts migration of GABAergic neuroblasts. Accordingly, we will determine whether this disruption reflects upstream changes in precursor identity or proliferation, compromised motility, or altered migratory environment. We expect autonomous changes in GABAergic migration as well as alterations in the migratory environment.

Specific Aim 3.  Does 22q11 deletion alter position and differentiation of GABAergic interneurons?

Rationale: GABAergic interneuron gene expression and connectivity is disrupted in schizophrenic patients. This may reflect initial failure of GABAergic neurons to acquire appropriate positions, processes or synapses. Accordingly, we will evaluate position of GABAergic irneurons as well as initial elaboration of dendrites and axons in deleted mice. The earliest generated GABAergic neurons may be mispositioned, and such disruptions may lead to inappropriate processes, connections and function.

Our data will indicate whether GABAergic precursors and progeny are compromised by a frequent genetic disorder associated with significant schizophrenia vulnerability. We will determine whether altered precursor identity, proliferation, migration or differentiation yield cortical circuits at increased risk for pathological change.