Schizophrenia Research Forum - A Catalyst for Creative Thinking

SfN 2007—Models Strut Their Stuff in San Diego

3 December 2007. Models were in vogue at this year’s annual meeting of the Society for Neuroscience in San Diego. Not the air-brushed ones that you might see in glossy magazines, mind you, but models that are far more attractive to researchers. Francine Benes, McLean Hospital, Belmont, Massachusetts, chaired a mini-symposium dedicated to animal models of schizophrenia. Presentations ran the gamut from genetic-based models to chemical and toxin treatments.

Weidong Li from the University of California, Los Angeles, started the symposium by describing the most recent addition to a growing list of DISC1 mouse models. Mutations in DISC1 (disrupted in schizophrenia 1) have been linked to schizophrenia and other major psychiatric illnesses, and the protein is believed to play a major role in neurodevelopment. To test whether DISC1 failure during development translates to deficits later in life, Li and colleagues have engineered a reversible, dominant-negative DISC1 construct that can be turned on and off at will. This reversible, inducible DISC1 mouse was just recently described in PNAS, and SRF has already outlined the major findings (see SRF related news story). Briefly, Li described how turning on the dominant-negative DISC1 during early development (postnatal day 7) causes problems for adult mice, including compromised spatial working memory, depression, and asocial behavior. The mouse supports the neurodevelopmental model of schizophrenia and could prove useful in teasing out exactly what developmental pathways are affected.

Another genetic-based model was described by Tobias Halene from RWTH Aachen University, Germany. This model is based on the glutamate hypothesis of schizophrenia, which suggests that NMDA-type glutamate receptor function is compromised in the disease (see SRF current hypothesis). Halene and colleagues bred transgenic mice that are NMDA receptor hypomorphs, meaning that they only produce about 5-7 percent of the normal levels of the NR1 glutamate receptor subunit. When put through a battery of behavioral and electrophysiological measurements, these animals showed some deficiencies compared to normal mice. The typical P20 and N40 sound-induced event-related potentials were higher and lower, respectively, than in wild-type animals (similar changes in analogous human P50 and N100 ERPs, have been proposed as endophenotypes of schizophrenia). In tests of behavior, the NMDAR hypomorphs spent more time in open sectors on an elevated maze, and they spent less time checking out new mice introduced into their environment. But the animals showed no difference in locomotor activity. Halene observed that previous publications have observed much higher locomotor activity in NMDAR-compromised animals, and he suggested that the environment in which the tests are made is crucial. In the elevated maze and the sociability test, he detected no locomotion difference, as measured by beam breaks, between hypomorphs and normal mice. Halene concluded that NMDAR deficiency results in a lack of behavioral inhibition that might mimic some of the symptoms and behaviors in schizophrenia.

The NMDA theme was also featured in several other presentations. Chalon Majewski-Tiedeken and colleagues the University of Pennsylvania use the NMDA antagonist ketamine to modulate NMDAR hypofunction. Ketamine is a widely used veterinarian anesthetic, but recreational abuse of the drug has been linked to emotional and behavioral disturbances, including anxiety, hallucinations, paranoia, and cognitive disruption, that are also experienced by people with schizophrenia. Ketamine binds noncompetitively to NMDA receptors in GABAergic, serotonergic, and noradrenergic neurons, but whether the drug induces any permanent anatomical damage is unclear.

Majewski-Tiedeken has addressed this by giving frequent, sub-anesthetic doses of ketamine to several strains of inbred mice. She reported that brain sections of treated mice tested positive for both apoptosis (caspase 3 immunolabeling) and neurodegeneration (de Olmos silver staining) in the CA3 layer of the hippocampus. She suggested that excitotoxicity, as a result of compensatory glutamate increase, and cell death may explain some of the long-lasting effects of ketamine exposure. This may sound counterintuitive, given that the NMDA antagonist memantine is currently approved for treating neurodegenerative conditions such as Alzheimer’s disease. Majewski-Tiedeken suggested that the situation may be highly complex and that in Alzheimer’s, stroke, or other conditions where a toxic insult has already occurred, glutamate antagonists may be protective at low doses but toxic at high doses.

From the same laboratory at U. Penn, Richard Ehrlichman reported that NMDAR antagonists can elicit in mice some of the same alterations in brain waves seen in schizophrenia patients. In humans these waves, or electrophysiological oscillations, are generally lumped into four main categories: theta (4-7.5 Hz), alpha (8-13 Hz), beta (14-30 Hz) and gamma (30 Hz and above). Disturbances in these bands, particularly the gamma, have been recorded in patients with schizophrenia and have been proposed as endophenotypes of the disease (see SRF related news story and SRF news story).

Ehrlichman described studies to determine if NMDA hypofunction or dopamine hyperfunction in mice can mimic some of the human endophenotypes—hyperactivity of dopaminergic neurons is another well-accepted hypothesis for schizophrenia (see SRF current hypothesis). He administered ketamine and amphetamine to mice to elicit hypo- and hyperfunction, respectively, and then used electroencephalograms (EEGs) to measure various frequency ranges. Ehrlichman recorded baseline EEGs and also evoked EEGs following an audible paired click. The EEG waveforms were band-pass filtered and averaged for each mouse.

He reported that ketamine had no effect on baseline wave powers except in the gamma frequency range where the power was increased. The NMDA antagonist also elicited decreases in evoked theta and alpha waves but increased gamma waves. These responses are consistent with gamma and theta changes seen in people with schizophrenia. He found that amphetamine had no effect on baseline power in any frequency range, but it did significantly decrease the power of the evoked theta wave. The findings suggest that dopaminergic hyperfunction alone is insufficient to recapitulate in mice the changes seen in human patients.

A slightly different angle on the dopamine hypothesis was offered by Alain Louilot, University Louis Pasteur, Strasbourg, France. Louilot and colleagues are interested in why latent inhibition is reduced in some people with schizophrenia. Latent inhibition (LI) is a phenomenon in which a conditioned response is reduced or even eliminated if the stimulus is first given without the condition (think how Pavlov’s dogs would have responded to a bell if it was originally rung in the absence of food). LI is believed to be important for processing sensory information, something that often presents difficulty to people with schizophrenia.

Louilot and colleagues wondered if LI in adults is related to problems in the hippocampus during neurodevelopment. To test this in rats, the researchers introduced a reversible lesion in the subiculum, the output center of the hippocampus, by injecting tetrodotoxin (TTX) at postnatal day 8. The idea is that this lesion would disrupt the normal development of the brain. The researchers then looked for electrophysiological abnormalities in neurons several stages downstream, specifically neurons in the anterior striatum that are innervated by midbrain dopamine neurons. Sixty-two days after TTX injection, the researchers measured in vivo electrical activity while testing latent inhibition. The authors found that developmental inactivation of the subiculum induced abnormalities of the LI-related dopaminergic response in the anterior striatum. The findings suggest that latent inhibition deficits in adults may have their origins in early developmental changes.

Barbara Gisabella and colleagues at McLean Hospital have used a similar strategy to probe the relation between GABAergic currents in pyramidal cells of layers CA2/3 of the hippocampus and input from the basolateral nucleus (BLa) of the amygdala. Previously, the Benes lab showed that there is loss of GABAergic current in the hippocampus following infusion of picrotoxin, a GABA-A antagonist, into the amygdala. Because altered GABAergic tone is thought to be a major facet of schizophrenia, this picrotoxin treatment could serve as a model for the disease.

To gain a better understanding of exactly what happens in the hippocampus following picrotoxin infusion, Gisabella has examined hippocampal slices. Her hypothesis is that increased activity from the BLa in response to GABA antagonism might cause changes in the membrane properties of fast-spiking interneurons in the hippocampus.

Gisabella reported that administration of picrotoxin to postnatal-day-30 rats led to altered electrophysiology in hippocampal slices taken 15 days later. In the CA2/3 layer she found decreased action potential duration, decreased resting membrane potential, and increases in spike frequency. In contrast, she reported that in the CA1 layer, electrical activity was similar in slices taken from saline- and picrotoxin-treated animals.

What might lead to shorter action potentials and more rapid firing of hippocampal neurons? Gisabella noted that postmortem studies of schizophrenia patients have revealed upregulation of the gene that codes for the hyperpolarization-activated (Ih) potassium channel in layer CA2/3 of the hippocampus. Could these channels contribute to the increased activity? Gisabella found that the Ih current amplitude was increased in hippocampal slices taken from picrotoxin-treated animals, and she proposed a model whereby blockage of GABA in the amygdala leads to an increase in Ih activity and an alteration of the intrinsic membrane properties of CA2/3 interneurons in the hippocampus. These findings could help shed some light on the mechanisms by which interneuron firing is altered in schizophrenia, she said.

Administering other chemicals, not necessarily neurotransmitter agonists, antagonists, or toxins to mice, might also mimic some of the pathology of schizophrenia. Patricia Tueting, University of Illinois, Chicago, described the use of L-methionine to induce DNA methylation and downregulation of key genes that have been implicated in schizophrenia, including those for reelin (see SRF related news story) and glutamic acid deacarboxylase 67 (GAD67), which is necessary for GABA synthesis (see SRF related news story).

Tueting reminded the audience that 30 years ago clinicians had figured that methionine would actually help schizophrenia patients and entered into a small trial to test that hypothesis. But after the amino acid was given to 11 patients, seven of whom actually got worse and four showed no improvement, the idea was dropped. We now know, suggested Tueting, that in schizophrenia DNA methyltransferase activity is elevated in GABAergic neurons, and since methionine is a precursor for S-adenosylmethionine, a methyl donor, the amino acid was probably feeding modification of methyl sensitive genes such as RELN.

Tueting tested this hypothesis by administering methionine to mice and looking at key downstream effects including loss of dendritic spines, which are crucial for the proper function of neural networks. Reelin is, in fact, important for maintenance of spines, and reelin heterozygous mice have both loss of spines and GAD67. Tueting reported that administration of methionine to mice over a 1- to 2-week period resulted in significant loss of spines on the apical dendrites of pyramidal cells in prefrontal cortex, which extend into the GABAergic layer. Tueting demonstrated that it was specifically spines that are located about 3 Sholl units from the cell body that were most affected, the same region that is most affected in reelin heterozygous animals (Sholl units measure the radius out from the cell body). The findings suggest that administration of methionine could be used as a simpler model of reelin deficit. Tueting did not say whether these mice have any behavioral or functional problems, but she did say that the effect was reversible. Withdrawal of methionine was followed about 12 days later by a return to normal spine density, giving the model some valuable flexibility.

Animal models can serve not only to study disease pathology but also to develop and refine treatments, as exemplified by the work of Cara Rabin, University of Pennsylvania. Using animal models, Rabin demonstrated how a long-term delivery system could be used to overcome a major problem in schizophrenia treatment: failure to adhere to medication. Rabin noted that 74 percent of schizophrenia patients are unable to adhere to medication within 2 years of starting on a prescription and that as relapses increase, it becomes more and more difficult for patients to gain stability.

Non-adherence may certainly be linked to adverse side effects, but they can also be attributed to the inconvenience of taking daily medication. Despite this, there has been little study done on using implantable, long-term delivery approaches, said Rabin. One of the reasons for this is that DEPOT-type drug treatments are irreversible, she suggested.

Rabin has developed a removable implant comprising a polymer of polylactic and polyglycolic acids (PLGA) and risperidone, a second-generation antipsychotic drug. She reported that these implants are stable, release drug over a period of at least 56 days, and are easily removed. They also are capable of modifying behavior in animal models, as measured by pre-pulse inhibition to the startle response and event-related potentials. Rabin suggested that this type of long-term delivery could lead to reduced morbidity and mortality from untreated psychosis and perhaps other chronic conditions.—Tom Fagan.

Comments on Related News


Related News: Gamma Band Plays a Sour Note in Entorhinal Cortex of Schizophrenia Models

Comment by:  Bita Moghaddam, SRF Advisor
Submitted 3 April 2006
Posted 3 April 2006

Cortical dysfunction in schizophrenia has been attributed to both inhibitory GABA and excitatory glutamate neurotransmission. Abnormalities in cortical GABA neurons have been observed primarily in the subset of GABA interneurons that contain the calcium-binding protein parvalbumin (PV). The glutamatergic dysfunction is suspected primarily because reducing glutamate neurotransmission at the NMDA receptors produces behavioral deficits that resemble symptoms of schizophrenia. These two mechanisms have been generally treated as separate conjectures when conceptualizing theories of schizophrenia. The paper by Cunningham et al. demonstrates that, in fact, disruptions in PV positive cortical GABA neurons and blockade of NMDA receptors produce similar disruptions to the function of cortical networks.

The authors used lysophosphatidic acid 1 receptor (LPA-1)-deficient mice which, they argue, are a relevant model of schizophrenia because these animals display sensorimotor gating deficits, a critical feature of schizophrenia. They demonstrate that, similar to schizophrenia, the number of PV positive GABA neurons is significantly reduced in LPA-1-deficient mice. Furthermore, the γ frequency network oscillation disruptions they observe in these animals are similar to those seen in wild-type mice treated with the NMDA antagonist ketamine. (γ oscillations have been associated with sensory processing and deficits in γ rhythm generation have been reported in patients with schizophrenia during performance of sensory processing tasks.) The disruptive effect of ketamine on γ oscillations was mediated by a decrease in the output of fast-spiking GABA interneurons causing a disinhibition (i.e., increased firing) of glutamate neurons. These findings are significant because they suggest that cortical NMDA hypofunction may cause the reported GABA interneuron deficits in schizophrenia.

View all comments by Bita Moghaddam

Related News: Gamma Band Plays a Sour Note in Entorhinal Cortex of Schizophrenia Models

Comment by:  Patricio O'Donnell, SRF Advisor
Submitted 7 April 2006
Posted 7 April 2006

Animal models of schizophrenia and other psychiatric disorders are receiving increasing interest, as they provide useful tools to test possible pathophysiological scenarios. Some models have been tested with a wide array of approaches and many others continue to develop. If one focuses on possible cortical alterations, a critical issue emerging from many different lines of research using several different models is the apparent contradiction between the hypo-NMDA concept and the data suggesting a loss of cortical interneurons. Is there a hypo- or a hyperactive cortex?

This conundrum has been present since earlier days in the postmortem and clinical research literature, but with the advent of more refined animal models, it may be time to provide a possible way in which these discrepant sets of data can be reconciled. Whether this was the authors’ intention or not, the article by Cunningham and colleagues is an excellent step in that direction. This study used mice deficient in lysophosphatidic acid 1 receptor, a manipulation that reduced the GABA and parvalbumin-containing interneuron population by about 40 percent and disrupted γ (rapid) oscillations in the entorhinal cortex. A key element in this study was the finding that a similar alteration in rapid cortical oscillations was observed with the noncompeting NMDA antagonist ketamine. There is a large body of evidence indicating that interneurons (in particular, the fast-spiking type that include parvalbumin-positive neurons) are critical for synchronization of fast cortical oscillatory activity. As fast oscillations can be envisioned as phenomena with deep impact on cognitive functions, these findings may have bearing on possible pathophysiological scenarios underlying cognitive deficits in schizophrenia. This article does provide a strong indication that antagonism of NMDA receptors may selectively target cortical interneurons. This is in agreement with the work of Bita Moghaddam, who has shown that noncompeting NMDA antagonists can indeed increase pyramidal cell firing and glutamate levels in the prefrontal cortex. Thus, it is conceivable that psychotomimetic agents such as PCP or ketamine exert their cognitive effects by impairing interneuronal activity, hampering the fine-tuning of pyramidal cell firing that is expressed as fast cortical oscillations.

View all comments by Patricio O'Donnell

Related News: Asynchrony and the Brain—Gamma Deficits Linked to Poor Cognitive Control

Comment by:  Richard Deth
Submitted 14 December 2006
Posted 15 December 2006

Schizophrenia is associated with dopaminergic dysfunction, impaired gamma synchronization and impaired methylation. It is therefore of interest that the D4 dopamine receptor is involved in gamma synchronization (Demiralp et al., 2006) and that the D4 dopamine receptor uniquely carries out methylation of membrane phospholipids (Sharma et al., 1999). A reasonable and unifying hypothesis would be that schizophrenia results from a failure of methylation to adequately support dopamine-stimulated phospholipid methylation, leading to impaired gamma synchronization. Synchronization in response to dopamine can provide a molecular mechanism for attention, as information in participating neural networks is able to bind together to create cognitive experience involving multiple brain regions.

View all comments by Richard Deth

Related News: Asynchrony and the Brain—Gamma Deficits Linked to Poor Cognitive Control

Comment by:  Fred Sabb
Submitted 12 January 2007
Posted 12 January 2007
  I recommend the Primary Papers

Cho and colleagues find patients with schizophrenia showed a reduction in induced gamma band activity in the dorsolateral prefrontal cortex compared to healthy control subjects during a behavioral task that is known to challenge cognitive control processes. Importantly, the induced gamma band activity was correlated with better performance in healthy subjects, and negatively correlated with higher disorganization symptoms in patients with schizophrenia. These findings help explain previous post-mortem evidence of disruptions in thalamofrontocortical circuits in these patients.

These findings tie together several different previously identified phenotypes into a unifying story. The ability to link phenotypes across translational research domains is paramount to understanding complex neuropsychiatric diseases like schizophrenia. Cho and colleagues provide an excellent example for connecting evidence from symptom rating scales with behavioral, neural systems and neurophysiological data. Although not specifically addressed by the authors, these data may have important implications for understanding the neural basis of thought disorder as well. Hopefully, these findings will provide a frame-work for examining more informed and specific phenotypes relevant to schizophrenia.

View all comments by Fred Sabb

Related News: On Again, Off Again—DNA Methylation, Genes, and Plasticity

Comment by:  David Yates
Submitted 18 April 2007
Posted 26 April 2007

Are these studies of relevance to the report from Israel that older men feed their mutations into the gene pool and this in part accounts for keeping the “schizophrenia gene” going despite poor fertility (Malaspina et al., 2002)? And might a comparison of the DNA of healthy siblings born before the mutations of an “older man” mutation with that of a sibling who got such a later mutation and developed schizophrenia reveal something of interest?

View all comments by David Yates

Related News: Genetics, Expression Profiling Support GABA Deficits in Schizophrenia

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 26 June 2007
Posted 26 June 2007

The evidence is becoming overwhelming that the GABA system disturbances are a critical hallmark of schizophrenia. The data indicate that these processes are present across different brain regions, albeit with some notable differences in the exact genes affected. Synthesizing the observations from the recent scientific reports strongly suggest that the observed GABA system disturbances arise as a result of complex genetic-epigenetic-environmental-adaptational events. While we currently do not understand the nature of these interactions, it is clear that this will become a major focus of translational neuroscience over the next several years, including dissecting the pathophysiology of these events using in vitro and in vivo experimental models.

View all comments by Karoly Mirnics

Related News: Genetics, Expression Profiling Support GABA Deficits in Schizophrenia

Comment by:  Schahram Akbarian
Submitted 26 June 2007
Posted 26 June 2007
  I recommend the Primary Papers

The three papers discussed in the above News article are the most recent to imply dysregulation of the cortical GABAergic system in schizophrenia and related disease. Each paper adds a new twist to the story—molecular changes in the hippocampus of schizophrenia and bipolar subjects show striking differences dependent on layer and subregion (Benes et al), and in prefrontal cortex, there is mounting evidence that changes in the "GABA-transcriptome" affect certain subtypes of inhibitory interneurons (Hashimoto et al). The polymorphisms in the GAD1/GAD67 (GABA synthesis) gene which Straub el al. identified as genetic modifiers for cognitive performance and as schizophrenia risk factors will undoubtedly spur further interest in the field; it will be interesting to find out in future studies whether these genetic variants determine the longitudinal course/outcome of the disease, treatment response etc etc.

View all comments by Schahram Akbarian

Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  John Roder
Submitted 30 November 2007
Posted 30 November 2007

Some observations on the new report by Li and colleagues: this work is the first to map subregions of DISC1 and to show that a region that binds Nudel and LIS1 is important in generating schizophrenia-like perturbations in vivo. The authors express DISC1 C-terminus in mice, which interacts with Nudel and LIS1. They showed less native mouse DISC1 associations with Nudel mouse following gene induction. This suggests a dominant-negative mechanism.

No data was shown on native DISC1 levels following induction. Work from the Sawa lab shows that if murine DISC1 levels are reduced in non-engineered mice using RNAi, severe perturbations in development of nervous system are seen (Kamiya et al., 2005); however, behavior was not measured in this study. Severe perturbations would be expected based on the neonatal ventral hippocampal lesion model. In this latter model early brain lesions lead to later impairments in PPI and other behaviors consistent with schizophrenic-like behavior.

They use a promoter only expressed in the forebrain, so it is puzzling they see expression in the cerebellum. Expressed DISC1 bound to endogenous mouse Nudel and LIS1, presumably exerting a dominant-negative effect. Induction of the C-terminus DISC1 at day 7, but not in the adult, led to deficits in working memory, the forced swim test, and sociability. It would have been reassuring if these tasks were validated using antipsychotics and antidepressants. It is not clear in this study why the female C57 was used as a standard opponent mouse, and what genders of DISC1 mice have been used. Even though young C57 females (6 weeks old) were used as neutral partners, the data might be interpreted also as impaired sexual motivation in DISC1-Tg-Tm7 mice.

The authors made an attempt to translate their mouse data (low sociability) into a human population and found an association between DISC1 haplotypes and social impairments in a Finnish population (n = 232 samples), which supports a DISC1 role in social behavior, one of schizophrenia's symptoms. It would be useful to distinguish deficits in social interactions and impaired sexual behavior.

Deficits in working memory are also an important schizophrenia endophenotype, and it would be interesting to measure how specific the cognitive deficit is in DISC1-Tg-Tm-7 mice, estimating associative memory in classical fear conditioning, for example.

Induction of the transgene early in development to day 7 resulted in small changes in dendritic complexity in granule cells in the dentate gyrus. It is surprising larger changes were not observed. The role of DISC1 in the adult self-renewing progenitor cells in the dentate switches, so that DISC1 acts as a brake for dendritic complexity and migration (Duan et al., 2007). Thus, reductions in DISC1 in the adult dentate gyrus granule cells lead to enhanced dendrite growth/complexity.

In the adult, DISC1 was shown to interact with Nudel in controlling adult neurogenesis and development. It is of interest that in the Li et al. paper the transgene also perturbs native DISC1 binding to Nudel at day 7 but not adult. Synaptic transmission was reduced in CA1. It would have been nice to see a recording from dentate granule cells in which changes in dendritic complexity were found.

References:

Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005 Dec 1;7(12):1167-78. Abstract

Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Abstract

View all comments by John Roder

Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  Akira Sawa, SRF Advisor
Submitted 3 December 2007
Posted 3 December 2007

DISC1 may be a promising entry point to explore important disease pathways for schizophrenia and related mental conditions; thus, animal models that can provide us with insights into the pathways involving DISC1 may be helpful. In this sense, the new animal model reported by Li et al. (Silva and Cannon’s group at UCLA) has great significance in this field.

They made mice expressing a short domain of DISC1 that may block interaction of DISC1 with a set of protein interactors, including NUDEL/NDEL1 and LIS1. This approach, if the domain is much shorter, will be an important methodology in exploring the disease pathways based on protein interactions. Although the manuscript is excellent, and appropriate as the first report, the domain expressed in the transgenic mice can interact with more than 30-40 proteins, and the phenotypes that the authors observed might not be attributable to the disturbance of protein interactions of DISC1 and NUDEL or LIS1.

Now we have at least five different types of animal models for DISC1, all of which have unique advantages and disadvantages: 1) mice with a spontaneous mutation in an exon, which seem to lack some, but not all, DISC1 isoforms, from Gogos’s lab (see Koike et al., 2006; Ishizuka et al., 2007); 2) mice with mutations induced by a mutagen from Roder’s lab (Clapcote et al., 2007); 3) transgenic mice that express a dominant-negative mutant DISC1 from Sawa’s lab (Hikida et al., 2007); 4) transgenic mice that express a dominant-negative mutant DISC1 in an inducible manner from Pletkinov’s lab (Pletnikov et al., 2007); and 5) the mice from Silva’s and Cannon’s labs.

It is impossible to reach a firm conclusion on how the Scottish mutation of the DISC1 gene leads to molecular dysfunction until the data from autopsied brains of patients in the Scottish family become available. Millar and colleagues have published data of DISC1 in lymphoblastoid cells from the family members and propose an intriguing suggestion of how DISC1 is potentially disturbed in the pedigree (Millar et al., 2005); however, this remains in the realm of hypothesis/suggestion from peripheral cells. Thus, it is very important to compare the various types of DISC1 animal models in approaching how disturbance of DISC1 in brain leads to the pathophysiology of schizophrenia and related disorders.

References:

Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7. Abstract

Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y, Clapcote SJ, Hookway C, Morita M, Kamiya A, Tomoda T, Lipska BK, Roder JC, Pletnikov M, Porteous D, Silva AJ, Cannon TD, Kaibuchi K, Brandon NJ, Weinberger DR, Sawa A. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry. 2007 Oct ;12(10):897-9. Abstract

Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron. 2007 May 3;54(3):387-402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. Abstract

Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2007 Sep 11; Abstract

Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science. 2005 Nov 18;310(5751):1187-91. Abstract

View all comments by Akira Sawa

Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  David J. Porteous, SRF Advisor
Submitted 21 December 2007
Posted 22 December 2007

On the DISC1 bus
You wait ages for a bus, then a string of them come one behind the other. First, Koike et al. (2006) reported that the 129 strain of mouse had a small detection of the DISC1 gene and this was associated with a deficit on a learning task. The interpretation of this observation was somewhat complicated by the subsequent recognition that the majority, if not all, major DISC1 isoforms are unaffected by the deletion, but this needs further work (Ishizuka et al., 2007). Then, Clapcote et al. (2007) provided a very detailed characterization of two independent ENU-induced mouse missense mutations of DISC1, showing selective brain shrinkage and marked behavioral abnormalities that in one mutant were schizophrenia-like, the other more akin to mood disorder. Importantly, these phenotypes could be differentially rescued by antipsychotics or antidepressants. The main finger pointed to disruption of the interaction with PDE4 to misregulate cAMP signaling (Millar et al., 2005; Murdoch et al., 2007).

Then, back-to-back came two variants of DISC1 transgenic models from Johns Hopkins University (Pletnikov et al., 2007; Hikida et al., 2007) (see also SCZ Forum). Both Pletnikov and Hikida overexpressed a truncated form of DISC1 under the control of the CaMKII promoter (in Pletnikov’s case with an inducible CaMKU promoter). Both groups reported brain structural and behavioral abnormalities that aligned rather nicely with the earlier work of Clapcote et al. (2007). Pletnikov et al. showed that neurite outgrowth was attenuated in primary cortical neurons. They also showed that endogenous DISC1, LIS1, and SNAP25, but not NDEL1 or PSD-95, was reduced in mouse forebrain.

Now, Li et al. (2007) introduce yet another transgenic DISC1 model mouse, this time overexpressing a carboxy tail fragment of DISC1, so the opposite end of the DISC1 molecule from that overexpressed by Pletnikov and by Hikida. Intriguingly, Li et al. (as with all the preceding models) report significant behavioral differences for wild-type littermates. The point of added interest and significance here is that by using an inducible transgenic construct, they could elicit behavioral abnormalities if carboxy terminal DISC1 was expressed on postnatal day 7 only, but not in adult life. What are we to make of this and how do the models align? Li et al. interpret their results to suggest that DISC1 plays a crucial role, through NDEL1 and LIS1, in postnatal (but not adult) brain development. This study obviously raises some key questions. What is the developmental window of DISC1 effect? How can the lack of effect in the adult be reconciled with the rather striking effect on neurogenesis consequent upon downregulation of DISC1 in the adult mouse brain reported by Duan et al. (2007). And if overexpressing 5’ (Hikida, Pletnikov) or 3’ constructs (Li) can elicit similar phenotypes as seen in ENU-induced missense variants within exon 2 (Clapcote), can we come up with a unifying explanation? Perhaps not yet, but these various mouse models certainly emphasize the value of a multi-pronged mouse modeling approach. Combinations of “null,” transgenic, inducible, and missense mutants will help dissect the underlying processes. These studies also suggest that a variety of DISC1 variants in humans might elicit rather similar and also subtly different phenotypes. Indeed, Li et al. try to link their findings on the mouse to human studies, but here I feel there is cause for caution. The genetic association referred to maps to a haplotype in a quite distinct region of DISC1 and the direct or indirect functional effect of the haplotype is far from clear. It is, however, conceptually unlikely that this risk haplotype has a specific or restricted effect on Nudel and/or Lis1 binding. The corollary between a genetic association for a selected, but poorly defined sub-phenotype of schizophrenia with a poorly defined behavioral phenotype in the mouse may be a corollary too far too soon. Finally, whereas the focus of attention by Li, Pletnikov, and Hikida has been on the well-established/neurodevelopmental role of NDEL1 (and LIS1), the potential role of PDE4B both in neurosignaling (related to behavior, learning, and memory) and possibly also neurodevelopment should not be overlooked. In this regard it is noteworthy that PDE4 interacts both with the head and the carboxy tail domain of DISC1 (Hannah et al., 2007) and this most likely contributes to the phenotype in all the models described to date.

References:

Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron. 2007 May 3;54(3):387-402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. Abstract

Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y, Clapcote SJ, Hookway C, Morita M, Kamiya A, Tomoda T, Lipska BK, Roder JC, Pletnikov M, Porteous D, Silva AJ, Cannon TD, Kaibuchi K, Brandon NJ, Weinberger DR, Sawa A. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry. 2007 Oct 1;12(10):897-9. Abstract

Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7. Abstract

Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, Ehninger D, Hennah W, Peltonen L, Lönnqvist J, Huttunen MO, Kaprio J, Trachtenberg JT, Silva AJ, Cannon TD. Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18280-5. Abstract

Millar JK, James R, Christie S, Porteous DJ. Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Mol Cell Neurosci. 2005 Dec 1;30(4):477-84. Abstract

Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Abstract

Murdoch H, Mackie S, Collins DM, Hill EV, Bolger GB, Klussmann E, Porteous DJ, Millar JK, Houslay MD. Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J Neurosci. 2007 Aug 29;27(35):9513-24. Abstract

Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2007 Sep 11; [Epub ahead of print] Abstract

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