Rational: Social deficits are disabling, treatment refractory symptoms of schizophrenia. The amygdala is thought to modulate this behavior, and disruption of NMDA receptor (NMDAR) mediated glutamate transmission has been implicated as well. However, a detailed understanding of the cellular and regional circuit mechanisms underlying social deficits is lacking. Hypotheses: We propose that disrupted development and functioning of glutamatergic inputs to NMDARs on basolateral amygdala (BLA) neurons can disrupt acquisition and maintenance of normal social behavior. Furthermore, increased resting activity, i.e. noise, in BLA leads to disruption of normal signal processing and reduced signal-to-noise ratio (SNR) for social inputs from cortico-limbic brain regions. Approach: We will use in vivo electroencephalography, local field potentials (LFP) and multiunit recording in in BLA and hippocampus during social behavior as well as voltage sensitive dye imaging (VSDI) and intracellular recordings in slices from mice with disrupted NMDAR signaling. Model systems will include mice with constitutive reduction in NMDAR1 expression (NRl-/-) that have deficits in EEG and social interactions, as well as mice with amygdala-selective reduction in NRl using NRIflox mice with AAV-Cre injections. Interpretation: Data will inform interpretation of regional brain activation using fMRI and surface EEG (Project 1) in schizophrenia and at risk subjects. We will also examine novel pharmacologic approaches for restoration of excitatory-inhibitory balance in BLA at rest and during social behaviors. Public Welfare Statement: People with schizophrenia have difficulty in social interactions, which is disabling and resistant to current treatments. A part of the brain called the amygdala is thought to modulate normal social interactions, and disruption of the neurotransmitter glutamate at a receptor called the NMDA receptor, has been implicated in causing problems with normal social interactions in schizophrenia. This project will determine if disruption of glutamate activity at NMDA receptors in amygdala in mice can cause social deficits, and if fixing that activity with new medications could restore normal social function .

Public Health Relevance

Schizophrenia is a disabling disorder and social deficits that are part of the negative symptoms are refractory to treatment. The amygdala circuitry is thought to modulate these behaviors, and disruption of NMDA receptor mediated glutamate neurotransmission has been implicated in these behaviors as well. However, a detailed understanding of the cellular and regional circuit mechanisms underlying these behaviors is lacking.

National Institute of Health (NIH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1)
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University of Pennsylvania
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Tatard-Leitman, Valerie M; Jutzeler, Catherine R; Suh, Jimmy et al. (2015) Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability. Biol Psychiatry 77:556-68
Billingslea, Eddie N; Tatard-Leitman, Valerie M; Anguiano, Jaynie et al. (2014) Parvalbumin cell ablation of NMDA-R1 causes increased resting network excitability with associated social and self-care deficits. Neuropsychopharmacology 39:1603-13
Stujenske, Joseph M; Likhtik, Ekaterina; Topiwala, Mihir A et al. (2014) Fear and safety engage competing patterns of theta-gamma coupling in the basolateral amygdala. Neuron 83:919-33
Likhtik, Ekaterina; Gordon, Joshua A (2014) Circuits in sync: decoding theta communication in fear and safety. Neuropsychopharmacology 39:235-6
Kumar, Manoj; Duda, Jeffery T; Hwang, Wei-Ting et al. (2014) High resolution magnetic resonance imaging for characterization of the neuroligin-3 knock-in mouse model associated with autism spectrum disorder. PLoS One 9:e109872
Likhtik, Ekaterina; Stujenske, Joseph M; Topiwala, Mihir A et al. (2014) Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat Neurosci 17:106-13
Duman, Ronald S (2014) Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin Neurosci 16:11-27