Coronin 1 Regulates Cognition and Behavior through Modulation of cAMP/Protein Kinase A Signaling

Abstract

The evolutionarily conserved protein coronin 1 is needed for activating the cyclic AMP signaling pathway in the brain and is important for cognition and behavior.

Abstract

Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic–AMP–protein kinase A–dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1–deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes.

Author Summary

Memory and behavior depend on the proper transduction of signals in the brain, but the underlying molecular mechanisms remain largely unknown. Coronin 1 is a member of a highly conserved family of proteins, and although its gene lies in a chromosome region associated with neurobehavioral dysfunction in mice and men, it has never been directly ascribed a specific function in the brain. Here we show that coronin 1 plays an important role in cognition and behavior by regulating the cyclic AMP (cAMP) signaling pathway. We find that when cell surface receptors are activated, coronin 1 stimulates cAMP production and activation of protein kinase A. Coronin 1 deficiency resulted in severe functional defects at excitatory synapses. Furthermore, in both mice and humans, deletion or mutation of coronin 1 causes severe neurobehavioral defects, including social deficits, increased aggression, and learning disabilities. Strikingly, treatment with a membrane-permeable analogue of cAMP restored synaptic plasticity and behavioral defects in mice lacking coronin 1. Together this work not only shows a critical role for coronin 1 in neurobehavior but also defines a role for the coronin family in regulating the transmission of signals within cells.