Compartmentalization of Cyclic Nucleotide Signaling in the Ventral Hippocampus Social deficits are key features of several neuropsychiatric disorders, such as autism, schizophrenia, and PTSD, yet no medicines are available to remedy these symptoms. Without acceptable social behaviors, our ability to attract a mate, acquire resources from society, and establish a safe/secure environment is severely compromised. When an individual lacks proper social behaviors, one is often ostracized. Social isolation worsens mental and physical health and increases mortality, particularly among the elderly and mentally ill. To make matters worse, social isolation further impairs subsequent social behaviors-thus, creating a vicious cycle. Despite the fact that appropriate social behaviors are vital to thriving in one's environment, little is understood of the molecular mechanisms that control social behaviors or how social experiences modify these signaling pathways. This hampers the development of effective therapeutics for social deficits. To develop effective treatments, we need to better understand the molecular mechanisms that underlie social deficits. Phosphodiesterase 11A (PDE11A) is an enzyme that breaks down cAMP and cGMP, and PDE11A may be an important molecular mechanism for regulating social behavior. We have shown that mice that lack PDE11A do not properly engage in social interactions and fail to form long-term memories involving social cues. PDE11A is almost exclusively expressed in a small area of the brain called the ventral hippocampus, but there is also a low level of expression in the dorsal hippocampus. Based on this distribution, we hypothesize that PDE11A4 regulates social behavior primarily by controlling cyclic nucleotides in the ventral hippocampus. Across the 3 aims, we take an integrative experimental approach by coupling in vivo genetic manipulations with in vivo behavioral tests as well as ex vivo molecular and biochemical endpoints.
In Specific Aim 1, we will determine where (VHIPP vs. dorsal HIPP) and when (adulthood vs. adolescence) PDE11A modulates social behaviors.
In Specific Aim 2, we will identify how social isolation modifies PDE11A compartmentalization and, thus, impairs subsequent social behaviors.
In Specific Aim 3, we will define the signals that control the subcellular localization of PDE11A. These innovative studies will provide much needed insight into the fundamental mechanisms of complex social behavior as well as the function and regulation of PDE11A in the brain. Targeting PDE11A may be a way to selectively restore cyclic nucleotide signaling in a specific brain region that regulates social behaviors, without affecting signaling elsewhere. This may relieve social deficits without causing unwanted side effects.
Deficits in social behaviors are devastating aspects of many neuropsychiatric disorders, including autism, schizophrenia, PTSD, and others. Currently, there are no medicines that treat these symptoms. This proposal seeks to better understand how compartmentalization of cyclic nucleotide signaling in the ventral hippocampal formation regulates social behaviors with the goal of identifying new therapeutic targets for social deficits
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|Hegde, Shweta; Capell, Will R; Ibrahim, Baher A et al. (2016) Phosphodiesterase 11A (PDE11A), Enriched in Ventral Hippocampus Neurons, is Required for Consolidation of Social but not Nonsocial Memories in Mice. Neuropsychopharmacology 41:2920-2931|
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