RAS proteins are critical regulators of mitosis and are mutationally activated in many human tumors. RAS signaling is also known to mediate long-term potentiation (LTP) and long-term memory formation in postmitotic neurons, in part through activation of the RAF-MEK-ERK pathway. The RAS effector RIN1 appears to function through competitive inhibition of RAS-RAF binding and also through diversion of RAS signaling to alternate pathways. We show that RIN1 is preferentially expressed in postnatal forebrain neurons in which it is localized in dendrites and physically associated with RAS, suggesting a role in RAS-mediated postsynaptic neuronal plasticity. Mice with an Rin1 gene disruption showed a striking enhancement in amygdala LTP. In addition, two independent behavioral tests demonstrated elevated amygdala-dependent aversive memory in Rin1(-/-) mice. These results indicate that RIN1 serves as an inhibitory modulator of neuronal plasticity in aversive memory formation.
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