Individuals with schizophrenia and other neuropsychiatric disorders suffer from abnormal social behaviors, for
which there are few effective treatments. Here we aim to gain insight into the brain mechanisms responsible for
such dysfunction, focusing on the role of altered patterns of neural network activity that may be amenable to
treatment with brain stimulation paradigms. We focus on the social memory (SM) deficits in the Df(16)A+/-
mouse model of the human 22q11.2 deletion syndrome, which confers one of the highest known genetic risk
factors for schizophrenia. Our studies during the present funding period demonstrate that the mouse SM deficit
results, at least in part, from abnormal activity of hippocampal CA2 pyramidal neurons, which are known to be
critical for SM. At the cellular level, CA2 pyramidal neurons in the Df(16)A+/- mice are hyperpolarized due to an
increase in the TREK-1 resting K+ current, leading to decreased excitability. Our in vivo recordings show that in
wild-type, but not Df(16)A+/- mice, CA2 pyramidal neurons act as detector of social novelty, with CA2 firing
differentially responding to a novel versus familiar mouse. Of particular interest, we found that pharmacological
and/or genetic inhibition of TREK-1 could rescue both SM and CA2 coding for social novelty in Df(16)A+/- mice.
Finally we found that upregulation of Mirta22/Emc10, a regulator of membrane protein trafficking that is de-
repressed in Df(16)A+/- mice due to microRNA dysregulation, is a key molecular consequence of the 22q11.2
deletion that contributes to abnormal SM. Here we aim to provide deeper insight into how alterations in CA2
function produce an abnormal form of brain oscillations known as sharp-wave ripples, events that are critical
for memory consolidation. We will examine how abnormal sharp-wave ripples affect SM, and whether
reinstatement of normal sharp-wave ripples by optogenetic brain stimulation can rescue SM. As sharp-wave
ripples are abnormal in CA1 of Df(16)A+/- mice, and as a significant fraction of sharp-wave ripples in CA1 arise
in CA2, we hypothesize that the deficit in SM in Df(16)A+/- mice may result from abnormal CA2 sharp-wave
ripples. Furthermore, we surmise that optogenetic activation of CA2 using appropriately shaped patterns of
light that can trigger normal SWRs in wild-type mice may reinstate normal SWRS in Df(16)A+/- mice, and this
may rescue SM. Finally to gain deeper insight into the link between molecular changes associated with the
22q11.2 genetic deletion and altered brain function, we will explore whether Mirta22/Emc10 upregulation
underlies CA2 dysfunction, including increased CA2 TREK-1 activity, abnormal social coding and abnormal
sharp-wave ripples. In this way we will provide a unified understanding linking the genetic, molecular, cellular,
network, and behavioral mechanisms that contribute to social cognitive dysfunction associated with a human
genetic mutation linked to neuropsychiatric disease, with the aim of identifying novel approaches to treatment
based on the rational design of brain stimulation paradigms.