Large amplitude, global EEG oscillations in the delta/theta frequency range are normally characteristic of slow-wave sleep. In schizophrenia, however, delta power is high during wakefulness in frontal and central regions. This has been termed a thalamocortical dysrhythmia. Many symptoms of schizophrenia can be induced by NMDAR antagonists;work in rats shows that a delta frequency dysrhythmia can be induced by injection of NMDAR antagonist into the thalamus. The first goal of our work is to understand how NMDAR antagonists generate this abnormality. Our preliminary results point to a cellular mechanism: cells of the nucleus reticularis (nRT) of the thalamus are hyperpolarized by NMDAR antagonist;this deinactivates T-type Ca2+ channels which then generate delta frequency bursting. Our second goal is to understand the molecular mechanism of this effect. Our preliminary results confirm in situ hybridization showing that thalamic cells contain a rare form of NMDAR subunit, NR2C. This subunit is weakly blocked by Mg2+ at resting potential and thus generates a significant inward current in response to ambient glutamate;block of this current leads to the hyperpolarization that produces delta- frequency bursting. Thus our work points to a molecular/cellular mechanism for dysrhythmia. The third goal of our work is to understand how dopamine interacts with these processes. Our preliminary results suggest that D2 action may be synergistic with NMDA hypofunction in producing dysrhythmia. We will study this process in vivo to determine whether the delta oscillations induced by NMDA hypofunction can be reduced by D2 antagonist. A critical aspect of the dysrhythmia hypothesis, as proposed by R. Llinas, is that subregions of the thalamus generate abnormal low frequency oscillations in associated subregions of cortex;this produces local deficits in information processing that underlie the symptoms of the disease. A final goal of our work is to test this hypothesis. We will use a CRE-recombinase method to produce postdevelopmental knockout of NMDARs in subregions of the nRT. We will test whether NMDAR knockout in anterior nRT can produce enhancement of delta power in the frontal/central regions affected in schizophrenia, without affecting occipital cortex. We will test whether behaviors mediated by these regions are selectively affected by these oscillations. Because the CRE- recombinase method produces chronic changes, it provides a model system for identifying the chronic processes that underlie schizophrenia and drug therapy. If successful, this mouse will model the EEG symptoms of schizophrenia and provide a system in which potential therapeutic targets can be identified, based on the known pharmacology of the thalamus, and then tested for their ability to reverse the EEG symptoms.
According to the dysrhythmia hypothesis of schizophrenia, the enhanced low frequency thalamocortical oscillation found in the disease causes many of the symptoms. The cellular and molecular causes of this dysrhythmia in the thalamus will be investigated. A major clue appears to be the ability of NMDA recent antagonists to mimic the dysrhythmia.
|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|
|Duan, Aranda R; Varela, Carmen; Zhang, Yuchun et al. (2015) Delta frequency optogenetic stimulation of the thalamic nucleus reuniens is sufficient to produce working memory deficits: relevance to schizophrenia. Biol Psychiatry 77:1098-107|
|Lisman, John E; Jensen, Ole (2013) The Î¸-Î³ neural code. Neuron 77:1002-16|
|Lisman, John (2012) Excitation, inhibition, local oscillations, or large-scale loops: what causes the symptoms of schizophrenia? Curr Opin Neurobiol 22:537-44|
|Zhang, Yuchun; Buonanno, Andres; Vertes, Robert P et al. (2012) NR2C in the thalamic reticular nucleus; effects of the NR2C knockout. PLoS One 7:e41908|
|Zhang, Yuchun; Yoshida, Takashi; Katz, Donald B et al. (2012) NMDAR antagonist action in thalamus imposes Ã½Ã½ oscillations on the hippocampus. J Neurophysiol 107:3181-9|
|Lisman, John E; Pi, Hyun Jae; Zhang, Yuchun et al. (2010) A thalamo-hippocampal-ventral tegmental area loop may produce the positive feedback that underlies the psychotic break in schizophrenia. Biol Psychiatry 68:17-24|