Social, Communication, and Cortical Structural Impairments in Epac2-Deficient Mice

Abstract

Deficits in social and communication behaviors are common features of a number of neurodevelopmental disorders. However, the molecular and cellular substrates of these higher order brain functions are not well understood. Here we report that specific alterations in social and communication behaviors in mice occur as a result of loss of the EPAC2 gene, which encodes a protein kinase A-independent cyclic AMP target. Epac2-deficient mice exhibited robust deficits in social interactions and ultrasonic vocalizations, but displayed normal olfaction, working and reference memory, motor abilities, anxiety, and repetitive behaviors. Epac2-deficient mice displayed abnormal columnar organization in the anterior cingulate cortex, a region implicated in social behavior in humans, but not in somatosensory cortex. In vivo two-photon imaging revealed reduced dendritic spine motility and density on cortical neurons in Epac2-deficient mice, indicating deficits at the synaptic level. Taken together, these findings provide novel insight into the molecular and cellular substrates of social and communication behavior.

Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions

“…Future studies that unravel the molecular mechanisms underlying the loss of Epac1 in fibrosis and COPD are warranted (Yokoyama et al, 2008c;Oldenburger et al, 2012). Knockout mice of either Epac1 or Epac2 as well as Epacs' double knockout mice (Shibasaki et al, 2007;Suzuki et al, 2010;Srivastava et al, 2012a;Yang et al, 2012) substantiate the notion that Epac is indispensable for proper functioning of pancreatic b-cells and neuronal functions to prevent the development of diabetes and Alzheimer's disease. Such studies support a link between the release of insulin from pancreatic b -cells and Epac2 (Shibasaki et al, 2007).…”

“…Currently, individual microRNAs are believed to act as pivotal modulators of mammalian functions during both development and disease (Filipowicz et al, 2008). Additional studies in Epac2-deficient mice indicate that Epac2 depletion is sufficient to induce impairments in social interactions, ultrasonic vocalization, and cortical structures (Srivastava et al, 2012a), suggesting that both Epac1 and Epac2 control Fig. 5.…”

Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens

“…It is, however, somewhat surprising that loss of function studies, such as using tissue from ER knockout mice, or RNAi approaches to silence specific receptor subtypes have not been used to elucidate the relative contribution of specific ERs to the regulation of dendritic spines. Future studies using conditional ER or aromatase knockout animals to isolate the actions of estrogens in a brain region and/or cell-specific manner, in combination with in vivo imaging approaches to examine dendritic spines (Bhatt et al, 2009;Srivastava et al, 2012b), will provide unprecedented insight into the contribution of centrally synthesized estrogens on the rapid modulation of synapse structure.…”

Recent Advances in the Discovery of Small Molecules Targeting Exchange Proteins Directly Activated by cAMP (EPAC)

“…63 Thus, targeting EPAC signaling pathway can be considered as a promising strategy for the treatment of various neurological disorders such as autism, anxiety and depression, schizophrenia and Alzheimer’s disease. 63–73 …”