Patients with neuropsychiatric disorders, such as panic/anxiety disorders, have altered sensorimotor gating responses, a differential emotionality profile and abnormal social behaviors. The objective of our second research line is to identify mouse genetic models and to understand the genetic mechanisms underlying aspects of neuropsychiatric disorders. Based on genetic studies in human population suffering panic disorder, we have selected candidate genes that might participate in the pathogenesis of the disease. Our initial studies are focusing on mice with overexpression of NTRK3 (TrkC, the high affinity receptor of neurotrophin 3), using pharmacological and behavioral strategies to better understand the nature of the behavioral abnormalities in these mice. Our hypothesis is that TrkC ligands regulate the development of LC NA neurons in vivo and that developmental alterations in LC may facilitate an anxiety prone phenotype and predispose to the development of panic disorder. We have demonstrated that overexpression of TrkC in mouse leads to an increase in number of catecholaminergic neurons in the LC and SN and show elevated anxiety and panic reaction. The open questions are now i/ if this effect is achieved by specifically promoting TH-positive neurons or by affecting survival, and ii/ if it affects other brain regions involved in fear circuits. We are studying the development and function of the fear system in these mice, using behavioral, electrophysiological, and cellular experimental approaches to determine the critical brain structures and time period as well as identify relevant morphological and molecular changes that determine anxiety behaviour.
We are studying the interaction between genetic and environmental influences (predisposing factors) on anxiety during the postnatal period.
Secondly, we focus on the identification of novel genetic factors that can impact anxiety behaviour during development. We are studying the role of nicotinic receptor subunits in the development of anxiety-like behavior. Mice overxpressing alpha 7, alpha 5, beta 2, or beta 4 subunits, are used to study the contribution of different nicotinic receptor subunits to (a) the expression of normal behaviors, (b) the sensitivity to the behavioral effects of panicogenic/panicolitic agents, and (c) the development of dependence and tolerance.
