As the most prevalent group of psychiatric diseases, anxiety disorders are chronic and disabling conditions that impose enormous costs on individuals and society. Anxiety disorders have complex polygenic etiologies with poorly understood underlying brain circuitries. Structures in the amygdala such as the basolateral complex are widely implicated in anxiety, but additional regions include insula cortex, medial prefrontal cortex, bed nucleus of stria terminalis, and hippocampus. Among several candidate genes, NMDA receptors (NMDARs), and GluN2B subunits in particular have been associated with anxiety. However, there is no clear picture of unique or converging molecular mechanisms that underlie these disorders. The lack of a mechanistic understanding precludes the identification of novel therapeutic targets and development of useful mouse models. These factors contribute to languishing efforts to develop drugs for pathological anxiety. This proposal seeks to test a novel molecular pathway that regulates anxiety in rodents, and test whether manipulations of this pathway can be anxiolytic. The hypothesis being tested is that Amyloid Precursor Protein Intracellular Domain Associated-1 (AIDA-1) regulates anxiety-related behaviors by controlling NMDAR function in ventral hippocampus (VH). AIDA-1 is a synaptic protein that controls GluN2B subunit function and NMDAR- dependent plasticity in the hippocampus. Preliminary findings indicate that AIDA preferentially regulates GluN2B function in VH. Behavioral testing reveals that AIDA-1 forebrain knockout mice (AIDA-1 cKO) only display reduced anxiety, and not the deficits in spatial and episodic memory expected from deficits in NMDAR function and hippocampal synaptic plasticity. Selective AIDA-1 knockdown in VH, but not in amygdala, recapitulate the reduced anxiety phenotype observed in AIDA-1 cKO mice. Our data support longstanding evidence of VH function in emotionality. The proposed studies will provide insight into AIDA-1 and NMDAR biology, and into functional differences present along the dorso-ventral axis of the hippocampus. Importantly, these experiments will provide insights into anxiety disorders, and may identify novel therapeutic targets for their treatment.

Public Health Relevance

Anxiety disorders are the most frequently diagnosed neuropsychiatric diseases in Western countries and impose enormous costs on individuals, society and the economy. Drug development has stalled and few novel therapeutic targets have been identified due to a limited mechanistic understanding of anxiety. The objectives of this proposal are to test that the synaptic protein AIDA-1 lies within a molecular pathway that regulates anxiety-related behaviors, and that components of this pathway represent novel therapeutic targets for anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
High Priority, Short Term Project Award (R56)
Project #
5R56MH115201-03
Application #
9691494
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Nadler, Laurie S
Project Start
2018-04-20
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
081266487
City
Bronx
State
NY
Country
United States
Zip Code
10461