Hippocampal CA2 sharp wave ripple oscillations in neuropsychiatric disease

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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.