Drd3 Signaling in the Lateral Septum Mediates Early Life Stress-Induced Social Dysfunction.
Shin S1, Pribiag H1, Lilascharoen V1, Knowland D2, Wang XY1, Lim BK3.
Early life stress (ELS) in the
form of child abuse/neglect is associated with an increased risk of
developing social dysfunction in
adulthood. Little is known, however, about the neural substrates or the
neuromodulatory signaling that
govern ELS-induced social dysfunction. Here, we show
that ELS-induced downregulation of dopamine receptor 3 (Drd3) signaling and its
corresponding effects on neural activity in the lateralseptum (LS) are
both necessary and sufficient to cause social abnormalities in
adulthood. Using in vivo Ca2+ imaging,
we found that Drd3-expressing-LS
neurons in animals exposed to ELS show blunted activity in response to social stimuli. In
addition, optogenetic activation of Drd3LS neurons
rescues ELS-induced social impairments.
Furthermore, pharmacological treatment with a Drd3 agonist, which
increases Drd3LS neuronal
activity, normalizes the social dysfunctions
of ELS mice. Thus, we identify Drd3 in the LS as a
critical mediator and potential therapeutic target for the social abnormalities
caused by ELS.