In schizophrenia (SZ), the power of low-frequency EEG oscillations (delta/theta; 1-7 Hz) is elevated in the awake state in subregions of the thalamocortical system. NMDAR antagonist induces similar low-frequency oscillations and also produces many of the symptoms of SZ, thus raising the possibility that the abnormal delta oscillations in SZ are causal in producing symptoms of the disease. Our previous work using the NMDA hypofunction model shows that T-type Ca channels and NR2C are critical for generation of abnormal delta oscillations. We further showed that optogenetically inducing delta oscillation in the nucleus reuniens of the thalamus is sufficient to interfere with working memory, a cognitive process that shows deficits in SZ. This supports the hypothesis that abnormal delta in SZ could be causal in generating disease symptoms. Independent support for this framework for understanding SZ has come from two genome-wide studies; these identified the same isoform of the T-type channel as a risk gene for SZ. Thus, there is strong rationale for further understanding of how abnormal delta can produce symptoms of SZ. Furthermore, elucidation of the cellular and molecular mechanisms may suggest new strategies for disease treatment.
In Aim 1, we will further analyze how optogenetic stimulation of the reuniens at delta frequency interferes with working memory. The experiments are designed to determine whether the oscillations interfere with encoding or recall processes. The goal of Aim 2 is to test, in vivo, our understanding of delta generation and to determine whether drugs that reduce delta ameliorate symptoms in an animal model. Our specific hypothesis is that drugs that inhibit T- channel function directly, or reduce their function by depolarizing cells (thus producing inactivation of T channels), will reduce delta oscillations and ameliorate behavioral deficits. We have developed an in vivo assay in which we can evoke delta oscillations by injection of ketamine into the thalamus; we will use this model to evaluate drugs for their ability to reduce the power of these oscillations. We will further test drugs using the Df(16)A+/- mice that have been generated to model the human chromosomal deletion 22q11.2 that is the largest known risk factor for SZ. Consistent with the importance of delta oscillations, these mice have elevated delta power in the awake state. With this model, we can test for drugs that reduce delta power and determine whether these drugs ameliorate the working memory deficits in these animals.
In Aim 3, we test a novel hypothesis about the negative symptoms of SZ, symptoms that have been particularly difficult to understand and treat. This explanation is built on a proposal by Graybiel/Surmeier according to which activity in the parafasicular/centro-medial (PF/CM) nucleus of the thalamus preferentially activates the indirect (NoGo) pathway of the basal ganglia. Activity in the indirect (NoGo) pathway is thought to inhibit behavior and could thus produce avolition. We will use optogenetic methods to test whether imposing delta oscillations in PF/CM produces avolition.

Public Health Relevance

Health Relevance Studies of schizophrenia patients show that the power of low frequency oscillations in the EEG is elevated. We have shown that this abnormality is likely to be causal in generating symptoms of schizophrenia. Our research is aimed at understanding the mechanisms of this oscillation and identifying therapeutic strategies for blocking the oscillations.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Buhring, Bettina D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brandeis University
Schools of Arts and Sciences
United States
Zip Code
Sasaki, Takuya; Piatti, Verónica C; Hwaun, Ernie et al. (2018) Dentate network activity is necessary for spatial working memory by supporting CA3 sharp-wave ripple generation and prospective firing of CA3 neurons. Nat Neurosci 21:258-269
Lisman, John; Buzsáki, György; Eichenbaum, Howard et al. (2018) Publisher Correction: Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat Neurosci 21:1018
Anticevic, Alan; Lisman, John (2017) How Can Global Alteration of Excitation/Inhibition Balance Lead to the Local Dysfunctions That Underlie Schizophrenia? Biol Psychiatry 81:818-820
Lisman, John; Buzsáki, György; Eichenbaum, Howard et al. (2017) Viewpoints: how the hippocampus contributes to memory, navigation and cognition. Nat Neurosci 20:1434-1447
Lisman, John E (2017) Locke's View of the Hard Problem of Consciousness and Its Implications for Neuroscience and Computer Science. Front Psychol 8:1069
Richard, Edwin A; Khlestova, Elizaveta; Nanu, Roshan et al. (2017) Potential synergistic action of 19 schizophrenia risk genes in the thalamus. Schizophr Res 180:64-69
Khlestova, Elizaveta; Johnson, Jon W; Krystal, John H et al. (2016) The Role of GluN2C-Containing NMDA Receptors in Ketamine's Psychotogenic Action and in Schizophrenia Models. J Neurosci 36:11151-11157
Lisman, John (2016) Low-Frequency Brain Oscillations in Schizophrenia. JAMA Psychiatry 73:298-9