Schizophrenia Research Forum - A Catalyst for Creative Thinking

Different Frequency, Same Wavelength?—Cortex-Hippocampal Communication and Schizophrenia

15 January 2009. Altered neurotransmission in the prefrontal cortex (PFC) may underlie various schizophrenia symptoms, but does the problem really originate in the cortex? Similar symptoms can be evoked in animals by damaging a deeper part of the brain early in development—the hippocampus—and this seems to impinge on behavior controlled by the PFC. Recent work shows why that might be. Reporting in the November 26 Journal of Neuroscience, researchers at Albany Medical College, New York, and the University of Pittsburgh, led by Patricio O’Donnell (now at the University of Maryland), find that while lesioning the hippocampus in young mice has no effect on the number of parvalbumin-expressing interneurons in the PFC, it does alter the ability of those cells to change their response over time to the neurotransmitter dopamine. The results indicate that the hippocampus somehow regulates maturation of PFC interneurons and hints that PFC abnormalities that emerge in human adolescence could be due to inadequate crosstalk between the hippocampus and the cortex.

Another recent study supports the idea that the hippocampus is a critical modulator of cortical activity. While these two regions of the brain are rarely on the same frequency—cortical neurotransmission oscillates in the γ frequency band (30-100 Hz), while hippocampal transmission occurs at the much lower theta band (4-8 Hz)—researchers led by Gyorgy Buzsaki at Rutgers University, Newark, New Jersey, found that the hippocampal theta oscillations entrain cortical γ rhythms. The finding raises the intriguing possibility that the hippocampus may be at least partly responsible for perturbed γ rhythms that are often found in people with, or at risk for, schizophrenia. That report was also published 26 November in the journal Neuron.

Hippocampal influence
O’Donnell and colleagues’ study focused on the neonatal ventral hippocampal lesion (NVHL) model of schizophrenia that was first introduced by Barbara Lipska, Daniel Weinberger, and colleagues at the National Institute of Mental Health, Bethesda, Maryland (see Lipska et al., 1993). Lipska and colleagues found that lesioning the ventral hippocampus in neonatal rats led to the emergence of behaviors akin to those seen when the medial prefrontal cortex was lesioned in adult animals. This led to the suggestion, now well established, that the ventral hippocampus somehow influences maturation of the prefrontal cortex.

To better understand this relationship, O’Donnell and colleagues studied PFC interneurons in rats following NVHL. Interneurons signal with the inhibitory neurotransmitter GABA (γ-aminobutyric acid) and have a modulating effect on transmission in the cortex. It has been suggested that reduced GABAergic activity in the brain of schizophrenia patients may lead to disturbed γ oscillations, which in turn may explain changes in perception, working memory, and behavior that accompany the illness (see SRF current hypothesis and related SRF online discussion).

To see if PFC interneurons are altered by NVHL, first author Kuei Tseng (now at Rosalind Franklin University, North Chicago, Illinois) and colleagues carried out histological analysis on sections of rat brain after NVHL. The authors found no difference in expression of interneuron markers parvalbumin and GAD67 between lesioned rats and sham-operated controls. Work by coauthor David Lewis and colleagues suggests that the parvalbumin-positive subpopulation of fast-spiking interneurons is selectively perturbed in schizophrenia (see SRF interview), but these new expression data suggest that the number of parvalbumin-positive interneurons remains unchanged after the hippocampal lesion. Likewise, the basic electrophysiological properties of the interneurons appeared unchanged, since their basic firing patterns, kinetics, and amplitudes were similar to those from control rat brain.

But when Tseng and colleagues examined interneuron response to dopamine, they found a different story. Fast-spiking interneurons are stimulated by dopamine agonists specific for the D2 dopamine receptor (see Tseng et al., 2007), but in NVHL rats fast-spiking neurons failed to respond to quinpirole, a D2 agonist. “Fast-spiking interneurons have a switch in the way they are modulated by D2 agonists—during adolescence interneurons acquire an ability to be strongly recruited by dopamine—but that switch doesn’t occur in these animals,” O’Donnell told SRF.

The results suggest that it is not frank neuronal loss but a change in the properties of interneurons, namely their maturation, that underlies the phenotype of the NVHL model. It is unclear what exactly that maturation switch entails, though this is something O’Donnell plans to pursue. “My guess is that either the profile of the receptor changes or the G protein coupled to the receptor changes,” said O’Donnell. He is also intrigued by recent reports that dopamine receptors can form different heterodimers (see SRF related news story) and that the maturation of the interneurons in adolescence may reflect the emergence of a different receptor profile, which is somehow blocked by early hippocampal lesions.

Riding the waves
In the second study, Gyorgy Buzsaki and colleagues correlated theta hippocampal rhythms with γ oscillations in multiple cortical regions. First author Anton Sirota and colleagues simultaneously measured neuronal firings and oscillations in multiple sites and found that the amplitudes of neocortical neuron firings were phase-locked to theta rhythms. This phase-locking occurred in both cortical interneurons and also pyramidal neurons and occurred during REM sleep and also when animals were running on an elevated maze. Interestingly, pyramidal and interneurons, while apparently phase-entrained by theta rhythms, were not in phase with each other.

Looking more broadly at groups of neurons, the researchers found that neocortical γ rhythm bursts are modulated by the theta rhythm as well. “Essentially this is telling us that hippocampal rhythms are synchronizing high-frequency oscillations in the cortex,” said O’Donnell. “It may help us understand the integration between the hippocampus and the rest of the cortex.”

Whether the modulation of γ rhythms by hippocampal theta rhythms is abnormal in schizophrenia, or even in the NVHL model, remains to be seen. “It is possible that abnormal activity in the hippocampus is driving deficits somewhere else,” said O’Donnell.—Tom Fagan.

Tseng KY, Lewis BL, Hashimoto T, Sesack SR, Kloc M, Lewis DA, O’Donnell P. A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. J. Neurosci. 2008, November 26;28:12691-12699. Abstract

Sirota A, Montgomery S, Fujisawa S, Isomura Y, Zugaro M, Buzsaki G. Entrainment of neocortical neurons and gamma oscillations by the hippocampal theta rhythm. Neuron 2008, November 26; 60:683-697. Abstract

Comments on Related News

Related News: SfN 2005: Cortical Deficits in Schizophrenia: Have Genes, Will Hypothesize

Comment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers

Related News: Dopamine Receptors: The Right Combination Unlocks Calcium Release

Comment by:  Christoph Kellendonk
Submitted 29 January 2007
Posted 30 January 2007
  I recommend the Primary Papers

The paper by Rashid et al. presents yet another interesting example of how dopamine D2 receptors may activate signaling pathways independent of the classical cAMP pathway, a finding that may have potential therapeutic implications. Most antipsychotic drugs that ameliorate positive symptoms antagonize D2 receptors, which may be also at the origin of many of the side effects associated with these medications. But, if antipsychotic action utilizes signaling pathways that are distinct from those responsible for the side effects we may have the chance to develop new compounds with higher specificity and reduced side effects. Observations such as those made in Rashid et al. are essential steps in this direction.

View all comments by Christoph Kellendonk

Related News: Dopamine Receptors: The Right Combination Unlocks Calcium Release

Comment by:  Eleanor Simpson
Submitted 29 January 2007
Posted 30 January 2007
  I recommend the Primary Papers

This is a very exciting paper. The concept of D1 and D2 cellular coexpression had been debated for a long time; with limited antibodies for these receptors available, investigators had found conflicting results, dependent on the method of detection used.

The authors recently described the existence of D1-D2 hetero-oligomers. Here they elucidate a possible function of such a complex. The authors begin with a very thorough biochemical characterization in HEK cells stably expressing either D1, D2, or both receptors, concluding that SKF83959 is a specific agonist for Gq/11 coupled D1-D2 receptor hetero-oligomers. By using striatal membrane preparations from wild-type, D1 mutant, or D2 mutant mice, the authors identify a D1-D2 Gq11 complex in the brains of mature mice.

The authors conclude by suggesting that D1-D2 receptor signaling may be altered in neuropsychiatric disease and that this should be explored. This may be a little premature, and perhaps some more fundamental characterization of this newly discovered complex should first be undertaken. The increase in GTPgS incorporation by 100 uM dopamine is modest compared to the increase observed with 100 uM SKF+Quin treatment. Since none of these experiments are under in vivo physiological conditions, it would be reassuring to see that this modest DA response is also blocked by SCH or RAC.

The fact that the D1-D2 Gq/11 complex was detected in 8-month-old mice but not 3-month-old mice is fascinating and begs the questions, when do these complexes form? How and why do they form? Both RT-PCR and primary culture experiments suggest that at least a fraction of neurons in the striatum coexpress D1 and D2 receptors in young adult mice. Does the number of coexpressing neurons increase with age? Or does hetero-oligomer coupling to Gq/11 increase with age? There is evidence that D1 receptor-Gs protein coupling is reduced in very old rats (Sugawa et al., 1996). Is the appearance of D1-D2 Gq/11 complexes in the striatum relevant to brain maturation, or does it relate to a decline in DA signaling efficiency?

View all comments by Eleanor Simpson

Related News: Model of Schizophrenia Cortical Deficits Reversed With Antioxidants

Comment by:  Barbara K. Lipska
Submitted 21 August 2014
Posted 22 August 2014

This is a highly original and exciting paper demonstrating that juvenile antioxidant treatment can be effective in preventing a number of severe deficits in the neonatal hippocampal lesion model of schizophrenia. The authors chose an unusual approach to reversing and preventing behavioral, electrophysiological, and neurochemical changes described in many previous papers as characteristic of this animal model as well as human schizophrenia (Lipska et al., 1993; Lipska and Weinberger, 2000; Tseng et al., 2009). First, they showed that the neonatal excitotoxic lesion of the hippocampus results in oxidative stress in the prefrontal cortex early in development, perhaps caused by the loss of projections from the ventral hippocampus to the prefrontal cortex during a critical period in development. Second, they were able to prevent a number of abnormalities that mimic certain aspects of human schizophrenia by treating presymptomatic animals with several classes of antioxidant drugs. These drugs have the potential to be effective in humans and offer a much needed alternative to the current therapeutic treatment of schizophrenia.

Early intervention in people at risk for schizophrenia has been at the forefront of research in recent years due to the increased emphasis in society on mental illness, but few realistic, effective, and safe solutions have been found. Breaking the vicious circle of the developmental trajectory and preventing long-term disability accompanying this illness are of utmost importance and have been well recognized (see, e.g., Lieberman et al., 2013). The results of the study by Cabungcal et al. may bring us closer to finding a better way of treatment but require a lot more work to be done. For instance, would we know whom to pretreat? How does smoking factor into the oxidative stress, and contribute or interact with these new potential medications? Are antioxidants proposed as the sole solution, or would they be considered additives to more traditional therapies? Are they really safe and effective in humans? We will be impatiently waiting for research addressing these questions.


Lipska BK, Jaskiw GE, Weinberger DR. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology . 1993 Aug ; 9(1):67-75. Abstract

Lipska BK, Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology . 2000 Sep ; 23(3):223-39. Abstract

Tseng KY, Chambers RA, Lipska BK. The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res . 2009 Dec 7 ; 204(2):295-305. Abstract

Lieberman JA, Dixon LB, Goldman HH. Early detection and intervention in schizophrenia: a new therapeutic model. JAMA . 2013 Aug 21 ; 310(7):689-90. Abstract

View all comments by Barbara K. Lipska