One way to investigate functions of specific neuronal circuits is by targeting key regulatory molecules which control plasticity and looking at relationships between plasticity within these circuits and behavior of an animal model. Since MAP kinase is required for plasticity in the hippocampus and it is highly expressed in the amygdala, we hypothesized that MAP kinase is an important regulator of neuronal plasticity in the fear circuitry. The goals of this project are: 1) characterization of MAP kinase role in the expression of innate fear and fear learning using mice with forebrain-restricted knockout of MAP kinase and Rap1, 2) finding specific neuronal population in the brain where MAP kinase activity alter expression of fear, 3) characterization of MAP kinase-dependent electrophysiological properties of these neurons, 4) identification of the downstream molecular substrates of MAP kinase that mediate changes in the neuronal properties. The following has been accomplished during the last fiscal year: 1) Mouse colonies producing animals with forebrain-restricted knockouts of MAP kinases Erk1 and Erk2, and double conditional knockout of Rap1A/Rap1B, have been established. 2) Biochemical analysis of the forebrain restricted knockout of Rap1 revealed a significant increase in the levels of both total and phosphorylated MAP kinase in the forebrain. Thus we have mice with either decreased (MAP kinase knockout) or increased (Rap1 knockout) activity of MAP kinase in the forebrain. 3) Behavioral analysis of Rap1 knockouts revealed reduced anxiety, normal contextual and impaired cued fear learning. These phenotypes may result from an increased MAP kinase activity in the forebrain.
