Low-Frequency Brain Oscillations in Schizophrenia

Understanding thebrainnetworks thatproduce thesymptomsof schizophrenia is a major goal of modern neuroscience. There is increasing evidence that brain function depends critically on oscillations, and ithas thereforebeenof interest todeterminewhether the oscillatorypropertiesof thebrain areabnormal in schizophrenicpatients. There is now considerable evidence that this is the case; indeed, both gamma frequency oscillations (30-80 Hz) and lowfrequency oscillations (delta oscillations of 1-4 Hz and theta oscillationsof5-10Hz) intheelectroencephalogram(EEG)showwellreplicated abnormalities butwith different relationships to the disease state. A reduction in task-evoked gamma power is present in unaffected relativesof schizophrenicpatients andmay thereforebe an endophenotype of the disease, but not a direct cause. In contrast, the increasedpowerof restingdeltaoscillations ispresentonly when thedisease is present andmay thereforebedirectly causal.1,2 Delta oscillations normally occur during slow-wave sleep and arise through an interaction between the thalamus and the cortex. During slow-wave sleep, the resting potential of thalamic cells becomeshyperpolarized. This hyperpolarization removes the inactivation fromT-typeCa2+channels,which thengenerateCa2+ spikes. Theseoccurat thedelta frequencyandpacethedelta frequencyEEG oscillations. In schizophrena, such oscillations occur during wakefulness in subregionsof the thalamocortical system.3Recentwork4 shows that the delta abnormality is seen in unmedicated patients and involves several Broadmann areas (8, 47, 7, and 37). It is difficult to study the mechanism of delta oscillations in schizophrenic patients, butmuch has nowbeen learned in rodents using the N-methyl-D-aspartate (NMDA) hypofunction model of schizophrenia. The basis of this well-established model is the observation thatacuteadministrationofNMDAreceptor (NMDAR)antagonists tohumansproducessymptomsnotverydifferent fromthat of schizophrenia.Moreover, copy number variants associatedwith schizophrenia and a genome-wide association study (GWAS) demonstratedthatseveralgenesaffectingNMDARfunctionareriskgenes for schizophrenia.5 Importantly,NMDARantagonistsproducedelta oscillations in both humans and rodents. This provides the rationale for using the NMDAR hypofunction model in rodents so that one can study the molecular, cellular, and network processes by which NMDAR antagonists produce delta oscillations. What has been learned is summarized in the Figure. Experiments show that a critical site of action of NMDAR antagonists is in thethalamus6 (moststudieshavebeenperformedonthenucleus reticularisofthethalamus,aninhibitorystructurethat interactswiththalamic relaynuclei toproduceoscillations). Specifically, injectionof an NMDAR antagonist into the thalamus produces delta oscillations in thenucleus reticularis andrelaynuclei,whichare thentransmittedto the cortex and hippocampus. It is puzzling that an antagonist of an excitatory transmitter should excite neurons, but thebasis of this effect isnowunderstood. Itwas foundthatanantagonistactsonanunusual typeofNMDAchannel,NR2C,which ispresent in the thalamus and in only a fewother brain regions. Unlike otherNMDARs,NR2C is not blocked by Mg2+ at the resting membrane potential. The ambient extracellular glutamate known to exist throughout the brain can generate a small inward current through NR2C and thus depolarize thalamic cells. When NR2C is blocked, the resulting hyperpolarization removes inactivation from T-type Ca channels, which then produce delta oscillations. The dopamine (receptor D2) antagonist depolarizes thalamic cells and thereby blocks abnormal delta oscillations,6perhapsexplainingthetherapeuticactionofthesedrugs. These results raise the question of whether abnormal delta frequency oscillations are sufficient to produce symptoms of schizophrenia. Recent work used optogenetics to address this question.2 Neurons inasmall thalamic relaynucleus, thenucleus reuniens,were transfected with channelrhodopsin, a protein that can excite neurons when illuminated. Rats were trained to perform a working memorytask,a formofmemoryaffected inschizophrenia.Onefunctionof thenucleus reuniens is to relay spatialworkingmemory information from themedial prefrontal cortex to the hippocampus.7 The resultsshowedthatwell-trainedanimalsweresuddenlyunabletoperform this task when reuniens cells were illuminated at delta frequency. If illuminationwas stopped, the ratswereonce again able to perform the task. Thus, when a large fraction of reuniens cells are causedtoburst repetitively, this is sufficient to “jam”normal communication through the reuniens (Figure). Such jamming may contribute to the “functional disconnection” between cortical regions that has been identified in schizophrenic patients.8 Two further lines of evidence lend support to this circuitbasedmodel.TheTchannel is critical fordeltageneration, andaspecific isoformof this channel (Cav3.3/CACNA1I) is oneof thevery few ion channels identified as a risk gene for schizophrenia in aGWAS.9 Moreover, the same isoformwas themost significant gene linked to theEEGdelta frequencyabnormality in schizophrenia.1Because this particular isoform is present predominantly in the nucleus reticularis, this nucleus may be the key to understanding thalamic malfunction in schizophrenia. Second, studiesof the restingblood flow inschizophrenia revealedelevatedactivityof thehippocampus.With theadventofhigh-resolution imagingmethods, this activitywas localized to justoneof theseveral subregionsof thehippocampus, the CA1 region.10 This hyperactivity could not have been driven by the main intrahippocampal input from CA3 because CA3 was not hyperactive. However, CA1 is unique among hippocampal regions in receiving input from the thalamus (in particular, the nucleus reuniens). Thus, hyperactivity of reuniens provides a straightforward explanation for the selective activation of CA1 in schizophrenia. This theory ties togethermanyobservationsabout schizophrenia, includingresults frombrain imaging,EEGmeasurements,GWAS, other evidence pointing to abnormalities in the glutamatergic system,5 the therapeutic action of dopamine antagonists, and the structural evidence of thalamic abnormality. But how far does this get us toward new treatment strategies? Perhaps the most obvious strategy would be to block the T-type Ca2+ channels that generatedeltaoscillations.A specific T-channel antagonisthasbeendeClinical Review& Education