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 both fear and cognitive behaviors. To investigate weather modulation of MAP kinase-dependent synaptic plasticity contributes to the control of fear and cognitive behaviors, we are analyzing mice with the forebrain-restricted knockouts of p42 MAP kinase, and Rap1 gene isoforms A and B. Rap1 is known to regulate p42MAP kinase. The goals of this project are: 1) Characterization of the role of MAP kinase in learning and fear behaviors using mice with forebrain-restricted knockout of MAP kinase and Rap1, 2) Identifying the specific neuronal population in the brain where MAP kinase and Rap1 regulate expression of fear, 3) Characterization of electrophysiological properties of these neurons, 4) Elucidating how Rap1 and MAP kinase regulate cellular properties (morphology and synaptic structure) of glutamatergic neurons. The following has been accomplished during the last fiscal year: 1) Behavioral analysis of p42 MAP kinase forebrain restricted knockout mice and double forebrain-restricted Rap1A and Rap1B knockout mice revealed impaired learning in both cued and contextual fear conditioning indicating that both Rap1 and p42 MAP kinase are required for synaptic plasticity in the amygdala. Moreover, mice with double forebrain-restricted knockout of Rap1A and Rap1B were found to have reduced anxiety-like behaviors. 2) Electrophysiological analysis of synaptic properties of the baso-lateral nucleus of the amygdala showed that Rap1 knockout mice have impaired synaptic plasticity and enhanced synaptic transmission between cortex and amygdala, suggesting that the strength of the cortico-amygdala synapses inversely correlates with fear. 3) We established a mouse primary neuronal culture to study effects of Rap1 and MAP kinase deletion of synaptic morphology.
