This project examines the inhibitory neural circuitry of the CA2 region of the hippocampus and its role in neuropsychiatric disorders, focusing on neurodevelopmental disease including schizophrenia (SCZ) and autism spectrum disorder (ASD). The motivation for this proposal comes from two independent findings. First, we have recently found that CA2 is crucial for social memory, the ability of an animal to recognize a conspecific. Given the altered social behaviors characteristic of SCZ and ASD, we postulated that pathological changes in CA2 function might be contributing factors. Indeed, two independent studies on the brains of individuals with SCZ and bipolar disorder have found a significant loss in the number of parvalbumin positive (PV+) inhibitory neurons in the CA2 region of the hippocampus, but not in neighboring hippocampal regions (CA1 and CA3). To examine the possible role of CA2 in SCZ, we examined a mouse model (Df(16)A+/- mice) of the human 22q11.2 deletion syndrome, a neurodevelopmental disorder that provides one of the strongest known genetic links with SCZ. Individuals harboring this deletion also display a number of autistic-like changes in social behaviors. The Df(16)A+/- mice were shown to have a number of cognitive changes associated with SCZ, including altered prepulse inhibition and contextual and working memory. Our preliminary results demonstrate that these mice also have a profound deficit in social memory. Remarkably, we find that the Df(16)A+/- mice show a specific reduction in PV+ inhibitory neurons in CA2, but no change in CA1 or CA3, identical to the results in human neuropsychiatric disorders. Moreover, the loss of inhibition in mice is first seen in late adolescence to early adulthood, similar to the developmental onset of SCZ. Here we will expand upon these initial findings by examining the importance of CA2 in the behavioral phenotypes of the Df(16)A+/- mice. We will first explore in more detail the function of CA2 inhibitory neurons that are targeted by the deletion mutation. We will also probe more deeply the behavioral changes in the Df(16)A+/- mice and ask whether we can rescue the behavioral changes by either silencing or activating CA2 in these animals. Thus the experiments we propose will both provide new insight into the neural circuitry and function of inhibition in the underexplored CA2 region of the hippocampus and will help determine the potential role of altered CA2 function in a mouse model of SCZ. These experiments offer the possibility of identifying new targets for treating disease, particularly as CA2 PNs display a unique pattern of gene expression not seen in other hippocampal areas. Given the changes in social behavior associated with other neuropsychiatric disorders, including ASD, our experiments may also provide general insights into basic brain mechanisms contributing to a variety of disorders of social behavior.

Public Health Relevance

Our recent studies show that the CA2 region of the hippocampus is crucial for social memory, the ability of an individual to recognize and remember others, which is impaired in certain neuropsychiatric disorders. As changes in CA2 neurons have been observed in the brains of individuals with schizophrenia and bipolar disorder, we aim to provide insight into the importance of altered function of CA2 by examining its role in a prominent mouse genetic model of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH106629-01A1
Application #
9030570
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Buhring, Bettina D
Project Start
2015-12-14
Project End
2020-11-30
Budget Start
2015-12-14
Budget End
2016-11-30
Support Year
1
Fiscal Year
2016
Total Cost
$419,795
Indirect Cost
$157,423
Name
Columbia University (N.Y.)
Department
Neurosciences
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Sun, Qian; Sotayo, Alaba; Cazzulino, Alejandro S et al. (2017) Proximodistal Heterogeneity of Hippocampal CA3 Pyramidal Neuron Intrinsic Properties, Connectivity, and Reactivation during Memory Recall. Neuron 95:656-672.e3
Leroy, Felix; Brann, David H; Meira, Torcato et al. (2017) Input-Timing-Dependent Plasticity in the Hippocampal CA2 Region and Its Potential Role in Social Memory. Neuron 95:1089-1102.e5