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A Model for Disrupted Sleep In Schizophrenia?

20 November 2012. A new study published in Neuron on November 8 finds that sleep architecture is altered in a rat neurodevelopmental model proposed to mimic some of the features of schizophrenia. A team of researchers led by Matt Jones of Eli Lilly and Company in Surrey, United Kingdom, describes a coordinated relationship between different types of cortical and hippocampal oscillations in non-REM (NREM) sleep in control rats, but demonstrates a decoupling of these oscillations in rats treated in utero with methylazoxymethanol-acetate (MAM).

Sleep disturbances are common in schizophrenia, and include alterations in both rapid eye movement (REM) and NREM sleep (Wulff et al., 2010). In fact, improved quality of sleep is rated as an important treatment goal by patients (Auslander and Jeste, 2002). Abnormal sleep architecture is correlated with cognitive deficits in schizophrenia, leading to the hypothesis that sleep problems may, in part, underlie the impaired cognition (Manoach and Stickgold, 2009).

Individual oscillation properties are preserved
In the current study, first authors Keith Phillips and Ullrich Bartsch investigated several prominent oscillations of NREM sleep that underlie memory consolidation—cortical delta waves (0.3-3 Hz), thalamocortical sleep spindles (10-15 Hz), and hippocampal ripples (120-250 Hz) (Diekelmann and Born, 2010)—using electroencephalography, local field potential, and unit recordings of rats. They studied the sleep architecture of two groups: control rats and those exposed to the mitotoxin MAM during embryonic development, a proposed neurodevelopmental model for schizophrenia. MAM treatment interferes with the division and migration of neurons, and researchers can target different cortical circuits by varying the dose and timing of delivery. Rats treated with MAM on embryonic day 17 show several features reminiscent of schizophrenia, including cognitive impairments, as well as glutamatergic and GABAergic dysfunction (Lodge and Grace, 2009; see also SRF related news story; SRF news story).

In the current study, MAM-17 rats displayed normal circadian rhythms and REM sleep, but showed a reduction in their amount of NREM sleep. The researchers next examined the neurophysiological features of this impaired NREM sleep, finding reduced delta wave power, and spindle density and amplitude in MAM rats at visual cortex recording sites. In contrast to these posterior abnormalities, the mechanisms of delta wave and spindle generation in motor cortex, as well as hippocampal ripple properties, were largely unaffected by MAM treatment.

Relationship between oscillations is altered
The researchers next analyzed the temporal relationship between oscillations. In control rats, delta wave coherence was observed between the motor and visual cortical electrodes, with the motor cortical delta waves preceding the visual cortical ones, consistent with the anteroposterior direction of travel reported previously (Massimini et al., 2004). However, this coherence was reduced in MAM-treated rats, suggesting an impaired propagation and synchrony of delta waves.

The phase locking, or timing, of thalamocortical spindles relative to delta waves was also impaired in MAM rats at motor cortex electrode sites, but preserved at visual cortex sites, consistent with a posterior disruption of network activity. In addition, the coordination between hippocampal ripples and prelimbic cortical spindles was disrupted in the MAM group. In the control group, ripple power peaks preceded those of spindles, and spindle power modulated ripple power, consistent with a prior study (Clemens et al., 2011). However, this modulation was either completely lacking or greatly reduced in MAM rats.

Phillips, Bartsch and colleagues then examined whether the spike timing of single units was altered by MAM treatment, finding that the timing of prelimbic cortical and hippocampal units was shifted, and that prelimbic cortical units were less phase locked to spindles in MAM rats than controls. In addition, in control rats, those units with the strongest spindle phase locking fired more spikes during ripples than the units that were not as strongly phase locked. However, this relationship was absent in MAM-treated rats, further suggesting reduced ripple-spindle coordination and hippocampal-prelimbic cortical decoupling during NREM sleep in MAM rats.

Thus, MAM rats exhibit impaired propagation of cortical delta waves and incorrectly timed spindle oscillations during NREM sleep, resulting in impaired coordination with hippocampal ripples and altered spike timing. As for a mechanism underlying the decoupling of oscillations during NREM sleep, the authors suggest that the abnormalities in parvalbumin interneurons observed both in schizophrenia and the MAM model may play a role, since these cells are involved in the generation of cortical oscillations (Lodge et al., 2009; Gonzalez-Burgos et al., 2011). The authors conclude that “our study serves to emphasize that disrupted thalamic-cortical-limbic network activity during sleep must therefore be considered alongside waking activity as a therapeutic target in schizophrenia and related diseases.”—Allison A. Curley.

Phillips KG, Bartsch U, McCarthy AP, Edgar DM, Tricklebank MD, Wafford KA, Jones MW. Decoupling of sleep-dependent cortical and hippocampal interactions in a neurodevelopmental model of schizophrenia. Neuron. 2012 Nov 8 ;76(3):526-33. Abstract

Comments on Related News

Related News: Dopamine Problems? Blame the Hippocampus

Comment by:  Anissa Abi-Dargham
Submitted 29 November 2007
Posted 29 November 2007

What struck me most about the paper of Lodge and Grace is the overall consistency of the body of work between the preclinical and clinical observations, even down to the effect size for the dopaminergic alteration. Dopamine release in schizophrenia is at least double that in controls; whether measured after amphetamine (on average 17 percent displacement of the benzamide radiotracer versus 7 percent in controls) (Laruelle et al., 1999) or at baseline (19 percent D2 occupancy by dopamine in patients versus 9 percent in controls) (Abi-Dargham et al., 2000), the increase in dopamine activity in VTA of the MAM rats reported here is also a doubling of what is measured in saline-treated rats.

This work presents an important contribution to the field because it clarifies the role of the hippocampus in one of the cardinal features of the disorder as modeled in MAM rats. The fact that MAM treatment is one of the most valid animal models of schizophrenia—it replicates many of the disturbances, neurochemical, cellular, dendritic, morphometric, and behavioral, observed in schizophrenia—makes the finding very compelling.

The role of an abnormal hippocampal node in an important circuit central to the pathophysiology of schizophrenia has face validity: there are now many converging lines of evidence in patients with schizophrenia for alterations in hippocampal volume, cytoarchitecture, function, and neurochemical indices. What this paper presents that is unique is evidence, in a valid model of schizophrenia, for an etiological link between the faulty hippocampus and the faulty VTA. The next step will be to test an association between pathology of the hippocampus and that of the VTA and related striatal output in patients with schizophrenia. This is a study we currently are conducting, and is an example of translational research where a theory gets support and contributions by going back and forth between preclinical and clinical testing. If there is an association in the same patients between the hippocampal pathology and dopamine dysregulation, it will suggest that what is described for the MAM model here may be true for schizophrenia, too, i.e., that the pathology of the dopamine system is driven by a faulty hippocampal input.


Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry. 1999;46:56-72. Abstract

Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A. 2000;97:8104-8109. Abstract

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Related News: Dopamine Problems? Blame the Hippocampus

Comment by:  Elizabeth Tunbridge
Submitted 20 December 2007
Posted 20 December 2007
  I recommend the Primary Papers

In their recent paper Lodge and Grace elegantly demonstrate that hyperactivity of the ventral hippocampus underlies the elevated number of spontaneously active ventral tegmental dopamine neurons, and the concomitant increase in amphetamine-induced locomotor activity, found in MAM-treated rats. Since neonatal MAM treatment recapitulates some of the neurochemical, anatomical, and behavioral abnormalities associated with schizophrenia, these findings raise the possibility that the abnormal subcortical dopamine function associated with this disorder might also result from hippocampal dysfunction.

These findings are consistent with a wealth of evidence suggesting that the hippocampus is a prominent site of dysfunction in the schizophrenic brain (reviewed in Harrison, 2004), and it will be exciting to see the results of the clinical studies described by Anissa Abi-Dargham above.

In the future, it will be important to try to integrate these findings with other models aiming to explain the subcortical dopaminergic hyperactivity seen in schizophrenia. One well-known hypothesis is that these abnormalities might result from hypofunction of the prefrontal cortex (PFC; Weinberger, 1987; Bertolino et al., 2000). Animal studies demonstrate that PFC activity impacts on striatal dopamine function (e.g., Shim et al., 1996) and vice versa (Kellendonk et al., 2006). Thus, it will be of interest to assess the relative contributions of hippocampal and prefrontal dysfunction to these subcortical abnormalities in schizophrenia. Such investigations will necessarily involve the use of both patient populations and appropriate animal model systems. A difficult question will be to establish whether any one of these three regions represents a site of a primary “lesion” in schizophrenia or, perhaps more likely, whether their dysfunction reflects abnormalities in the circuits that link them.


Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, Frank JA, Pickar D, Weinberger DR. The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology. 2000 Feb;22(2):125-32. Abstract

Harrison PJ. The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl). 2004 Jun;174(1):151-62. Epub 2004 Mar 6. Review. Abstract

Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, Moore H, Kandel ER. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. 2006 Feb 16;49(4):603-15. Abstract

Shim SS, Bunney BS, Shi WX. Effects of lesions in the medial prefrontal cortex on the activity of midbrain dopamine neurons. Neuropsychopharmacology. 1996 Nov;15(5):437-41. Abstract

Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987 Jul;44(7):660-9. Abstract

View all comments by Elizabeth Tunbridge

Related News: ICOSR 2009—Psychosis: Is It All From Your Hippocampus?

Comment by:  David Yates
Submitted 25 April 2009
Posted 5 June 2009

Might it be helpful to reflect upon the schizophrenia that comes after epilepsy? I am not clear whether or not there were familial studies to discover any greater incidence in relatives, but may there have been postmortem tissue studies around the temporal lobes, that would have included hippocampus structures, which might connect with the current studies.

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Related News: ICOSR 2009—Psychosis: Is It All From Your Hippocampus?

Comment by:  David Oberlander
Submitted 16 April 2009
Posted 5 June 2009

Isn't it true that schizophrenia can also be considered a 'hypo-glutamatergic' state? Would AMPA-receptor upmodulators (so-called ampakines) have a role given this hypothesis? Specifically in that I seem to recall looking at slides of BDNF/NGF induction after these AMPA upmodulators were given. These neurotrophic effects affect hippocampus size, albeit in a distinct way from the neurotrophism of SSRIs. These AMPA receptor modulators also produce some improvement in cognitive skills.

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Related News: ICOSR 2009—Psychosis: Is It All From Your Hippocampus?

Comment by:  Hakon Heimer
Submitted 6 June 2009
Posted 6 June 2009

Reply to David Oberlander

Ampakines continue to show the ability to rescue cognitive deficits in animal studies (e.g., in a PCP model of schizophrenia by Broberg et al., 2009; and in a nonhuman primate sleep deprivation study by Hampson et al., 2009). However, a placebo-controlled clinical trial with the ampakine CX516 as an add-on to either clozapine, olanzapine, or risperidone did not produce cognitive benefits in schizophrenia patients (Goff et al., 2007).

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