Immediate Communication

Molecular Psychiatry (2004) 9, 35–41. doi:10.1038/

Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors

S A Brody1, S C Dulawa1,*, F Conquet2, and M A Geyer1,3

  1. 1Department of Neuroscience, University of California, San Diego, La Jolla, CA, USA
  2. 2GlaxoWellcome Experimental Research, IBCM, University of Lausanne, Lausanne, Switzerland
  3. 3Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

Correspondence: Dr MA Geyer, PhD, Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA. E-mail:

*Current address: Center for Neurobiology & Behavior, Columbia University, New York, NY 10032, USA.

Current address: Addex Pharmaceuticals, 1228 Plan les Ouates, Geneva, Switzerland.



The glutamate hypothesis of schizophrenia derived from evidence that phencyclidine, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, produces schizophrenia-like symptoms in healthy humans. Sensorimotor gating, measured by prepulse inhibition (PPI), is a fundamental form of information processing that is deficient in schizophrenia patients and rodents treated with NMDA antagonists. Hence, PPI is widely used to study the neurobiology of schizophrenia. As the use of PPI as a model of gating deficits in schizophrenia has become more widespread, it has become increasingly important to assess such deficits accurately. Here we identify a possible role of mGluR5 in PPI by using wild type (WT) and mGluR5 knockout (KO) mice of two different background strains, 129SvPasIco and C57BL/6. In both strains, PPI was disrupted dramatically in the mGluR5 KO mice throughout a range of interstimulus intervals and sensory modalities. The present findings further support the glutamate hypothesis of schizophrenia and identify a functional role for mGluR5 in sensorimotor gating.


PPI, metabotropic glutamate, mGluR5, startle, prepulse inhibition, knockout mouse

Prepulse inhibition of the startle response (PPI) provides an operational measure of sensorimotor gating, a process by which an organism filters extraneous information from the internal and external milieu.1,2 In healthy humans, rodents, or nonhuman primates, the prepulse stimulus serves to attenuate the motor response to the pulse.3 PPI deficits are found in a number of psychiatric populations, most notably patients with schizophrenia, obsessive–compulsive disorder, and Tourette's syndrome.4 As a model of the gating deficits in schizophrenia, PPI is believed to have face, construct, and predictive validity.5,6 In humans, PPI is measured via electromyographic recordings of the eyeblink response at the orbicularis oculi below the eye.7 In rodents, startle can be measured as the whole-body flinch. Glutamate, dopamine, and serotonin have been implicated both in the etiology of schizophrenia and the modulation of PPI.5 Effective antipsychotic agents appear to ameliorate PPI deficits in some patients with schizophrenia and in rodents given psychotomimetic compounds.4,5

The glutamate hypothesis of schizophrenia is derived from evidence that phencyclidine (PCP) and ketamine, noncompetitive N-methyl-D-aspartate (NMDA) antagonists, produce schizophrenia-like symptoms in healthy humans.8,9 Administration of these same compounds to rodents10,11 or nonhuman primates12 reduces PPI. The actions of glutamate, however, are mediated by both ionotropic and metabotropic receptors (mGluRs; activating second messenger system cascades involving GTP-binding proteins). Molecular cloning has identified eight metabotropic receptor subtypes, known as mGluR1-8.13 These receptor subtypes are divided into three groups based on sequence homologies and pharmacological properties.13 Group I includes mGluR1 and mGluR5, which are coupled positively to phospholipase C13 and are among the mGluRs14 concentrated in brain regions that regulate PPI.15

Specifically, mGluR5 is concentrated in the striatum, nucleus accumbens, olfactory tubercle, hippocampus, deep cerebellar nuclei, and cerebral cortex.16 Many of these structures, including the striatum, nucleus accumbens, and hippocampus, are known to modulate PPI.15 Furthermore, it has recently been noted that there is increased neuronal mGluR5 in pyramidal layers of area 11 in the prefrontal cortex of patients with schizophrenia.17 It has also been suggested that the mGluR5 gene on chromosome 11 might be relevant to an abnormal translocation linked to schizophrenia18 and other disorders such as Down syndrome.19 On the basis of this existing evidence, we hypothesized that a mouse lacking mGlu5 receptors (mGluR5 knockout (KO)) would exhibit an alteration in PPI.



Gene targeting

mGluR5 KO mice were generated as previously described.20 The absence of mGluR5 was confirmed with an mGluR5 antibody (Upstate Biotech). Mutants were detected by Southern blot by cutting the genomic DNA with EcoRI resulting in a wild type (WT) band of 5.1 kb and a mutated band of 2.2 kb after hybridization with an internal probe.


Subjects were mGluR5 KO (between 21 and 31 g, mean weight: 27 g) and WT (between 21 and 28 g, mean weight: 24 g) mice of two different background strains. All mice were bred homozygously at IFFA CREDO (a Charles River facility) in France and shipped to San Diego, CA. Upon arrival in San Diego, mice were housed by genotype in groups of one to four per cage with access to food and water and a reversed 12L : 12D schedule (lights off at 0900). A minimum of 1 week acclimation to the San Diego facility preceded behavioral testing. All experiments were carried out in accordance with the NIH guide for the care and use of laboratory animals (NIH Publication No. 8023). All efforts were made to minimize animal suffering and to reduce the number of animals used.

Male GluR5 WT and KO mice were tested at N5, 92% 129SvPasIco and 8% C57BL/6 ('129SvPasIco') or 92% C57BL/6 and 8% 129SvPasIco ('C57BL/6'). A total of 17 KO (nine 129SvPasIco and eight C57BL/6) and 20 WT mice (10 of each background), 9–11 weeks old were first tested for PPI. At 13–15 weeks old, the same mice were tested with multiple pulse intensities followed 3 weeks later by a test involving multiple interstimulus intervals. Additionally, the 129SvPasIco mice were tested with multiple modalities three more weeks later.


Behavioral testing used four startle chambers (San Diego Instruments, San Diego, CA, USA), as described previously.11,21 Briefly, each ventilated, illuminated chamber contained a clear, nonrestrictive Plexiglas cylinder resting on a platform and a high-frequency loudspeaker that produced both a continuous background noise of 65 dB and the various acoustic stimuli. Whole-body startle responses of the mouse caused vibrations of the Plexiglas cylinder. These vibrations were converted to analog signals by a piezoelectric transducer attached to the underside of the platform, and then digitized and stored by a computer. Monthly calibrations were performed on the chambers to ensure the accuracy of all acoustic stimuli and measurements.

Test sessions

Test sessions began with a 5-min acclimation period during which the background noise (a 65-dB white noise) was presented alone. Presentation of the 65-dB background noise then continued throughout the remainder of the test session. The initial acclimation period was followed by two to four blocks of trials, with an average intertrial interval of 15 s (and a range of intertrial intervals of 7–23 s). Block one consisted of six STARTLE (a 40-ms 120-dB broadband burst) trials; block(s) two (and, where presented, three) contained six trials of each type described below. When presented, block four consisted of six STARTLE trials.

Basic characterization

Four trial-types were presented during blocks two and three in a pseudorandomized sequence with six of each trial type per block. These trial types included: a 40-ms broadband 120-dB burst (STARTLE) and three distinct intensities of PREPULSE trials in which 20-ms-long prepulses (consisting of broadband bursts of 69, 73, or 77 dB) preceded the startle stimulus by an interstimulus interval of 100 ms (prepulse onset to pulse onset). The test session lasted for a total of 23 min and contained 72 trials.

Pulse intensities

To determine startle threshold and to verify that none of the mice were startling to the prepulses, mice were exposed to startle stimuli ranging from 65 to 120 dB. Each of nine distinct trial-types was presented six times in the course of this session. Following the first block of six STARTLE stimuli (40 ms long bursts of 120-dB broadband white noise), all trial types were presented in a pseudorandom order during the second block. Each trial consisted of a 40-ms broadband burst of one of the following intensities: 65, 69, 73, 77, 85, 90, 100, 110, or 120 dB. The session contained a total of 60 trials and lasted 20 min.

Interstimulus intervals

In humans, PPI is elicited at interstimulus intervals of 50–500 ms (onset of prepulse to onset of pulse3,7). In mice, PPI is typically examined using a similar interstimulus interval range with an optimum of 100 ms (see eg Varty et al22). To examine whether the WT and mGluR5 KO mice exhibited maximal PPI on the same timescale, PPI was observed across a range of interstimulus intervals. Eight trial-types were presented in four blocks. As described above, blocks one and four consisted of six STARTLE trials. Blocks two and three each contained six presentations of the following trials in a pseudorandom order: the 120 dB STARTLE; and seven distinct PREPULSE trials in which 20-ms 73-dB stimulus preceded the STARTLE by 50, 100, 200, 250, 300, 400, or 500 ms from prepulse onset to the onset of the STARTLE stimulus.

Equal startle

Owing to the fact that the mGluR5 WT and KO mice exhibit markedly different startle levels from one another, it was necessary to determine whether the observed PPI deficit was a function of startle magnitude. The data from Experiment 2 were used to determine the dB level at which the startle magnitude of the 129SvPasIco KO mice was equivalent to the startle magnitude of the 129SvPasIco WT mice elicited by a 120-dB PULSE. Only the 129SvPasIco mice were used in this experiment because the exaggerated startle in the C57BL/6 KO mice was so great that equivalent magnitudes could not be achieved by adjusting the stimulus intensity. Examination of the data from the multiple pulse intensities revealed that the response of the KO mice to a 105-dB stimulus was equivalent to that produced by the WT mice to a 120-dB stimulus. Therefore, four trial-types were presented: either a 40-ms broadband 120-dB burst (presented to the mGluR5 WT mice) or a 40-ms broadband 105-dB burst (presented to the mGluR5 KO mice) (STARTLE); three PREPULSE trials in which 20-ms 69, 73, or 77 dB prepulses preceded the startle stimulus by 100 ms.


The experiments described thus far all utilized auditory stimuli. PPI, however, is a multimodal phenomenon.3 To ensure that the KO mice were not experiencing a simple hearing deficit, we examined PPI across a variety of modalities by utilizing a mixture of visual prepulses (using a light cue), tactile pulses (using an airpuff), and auditory stimuli. Trial-types were: the 120-dB STARTLE; a 30-ms 40-psi airpuff delivered through a tube inserted into one end of the Plexiglas cylinder; a 20-ms 73-dB prepulse followed by one of 120 dB; a 77-dB prepulse followed by the airpuff after 100 ms; a 100-W light on for 100 ms and then off for 100 ms prior to the airpuff; the same light stimulus followed by a 120-dB STARTLE.

Data analysis

Startle magnitude was calculated as the average response to the STARTLE trials presented during blocks two and/or three of the session. PPI was calculated as both percentage and difference scores.21 In 129SvPasIco mice, both measures of PPI yielded similar results; in C57BL/6 mice, the marked increases in startle made difference scores uninterpretable. All scores are therefore presented as percentage scores. Appropriate two-way ANOVAs (with gene and, where present, strain as between subjects factors and trial type as a within subjects factor) were followed, when significant, by Student–Newman–Keul post hoc tests. Significance was determined by exceeding an alpha level of less than 0.05.



Experiment 1—basic characterization

PPI: A main effect of genotype (F[1,33]=31.32, P<0.0001) indicated that the PPI of the KO mice was severely disrupted, while a main effect of strain (F[1,33]=4.78, P<0.05) indicated that the C57BL/6 mice had elevated PPI relative to the 129SvPasIco mice (Figure 1). Although there was a significant interaction between prepulse intensity and genotype (F[2,66]=19.12, P<0.0001), further analysis using the Student–Newman–Keul test revealed that the PPI of the mGluR5 KO was significantly less than the WT at all three prepulse intensities (pp4, pp8, and pp12). A separate Student–Newman–Keul test revealed that a significant interaction between intensity and strain (F[2,66]=3.67, P<0.05) was due to the fact that the PPI of the C57BL/6 mice was higher than that of the 129SvPasIco mice at a prepulse of 4 dB above background.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

PPI and startle magnitude. (a) Graph depicts PPI values for mGluR5 WT and KO mice on a C57B1/6J background at three different prepulse intensities (69, 73, and 77 dB). Inset shows the startle magnitude of the same mice. White bars denote WT values, black bars denote KO values. Values are meansplusminusSEM. *P<0.05 (b) Graph depicts PPI values for mGluR5 WT and KO mice on a 129SvPasIco background at three different prepulse intensities (69, 73, and 77 dB). Inset shows startle magnitude for the same mice.

Full figure and legend (61K)

Startle: Main effects of genotype (F[1,33]=37.88, P<0.0001) and strain (F[1,33]=12.54, P<0.005) were found (Figure 1, inset). These results indicated that the KO mice had a larger startle response to the 120-dB pulse than did the WT mice. In addition, the 129SvPasIco mice exhibited a higher startle response than the C57BL/6 mice. The strain by genotype interaction approached but did not reach statistical significance (F[1,33]=3.16, P=0.0845).

Experiment 2—multiple pulse intensities

Although the deficit in PPI observed in mGluR5 KO mice is consistent with a reduction in sensorimotor gating, alternative explanations needed to be considered. The elevated startle reactivity in the KO mice could signify a reduced threshold for startle elicitation such that the KO mice might have startled in response to the prepulse stimuli. We therefore measured startle responses elicited by various acoustic intensities. Main effects of both genotype (F[1,31]=25.92, P<0.0001) and strain (F[1,31]=6.64, P<0.05) were found. A marginal strain by genotype interaction (F[1,31]=4.10, P<0.0515) was also evident, as were an intensity-by-gene interaction (F[9,279]=18.76, P<0.0001), an intensity by strain interaction (F[9,279]=5.52, P<0.0001), and an intensity-by-strain-by-gene interaction (F[9,279]=3.87, P<0.001). A Student-Newman-Keul analysis revealed that when presented with the background noise of 65 dB, the C57BL/6 mice showed higher basal motor activity than did the 129SvPasIco mice. Nevertheless, the KO and WT mice reacted comparably to the background noise and startled comparably to all of the stimuli 4–25 dB above background. Beginning at 90 dB (ie 25 dB above background), the KO mice of both strains show a higher startle response than do the WT mice. Since the most intense prepulses used in the above experiments were 77 dB, it does not appear that the KO mice were startling in response to the prepulse stimuli. The 129SvPasIco mice exhibited a higher startle response than the C57BL/6 mice beginning at 100 dB (Figure 2).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Pulse intensities. Startle magnitude at multiple pulse intensities ranging from 65 to 120 dB. Circles denote C57B1/6J WT, squares denote C57B1/6J KO, upward triangles denote 129SvPasIco WT, and downward triangles denote 129SvPasIco KO mice. Values are meansplusminusSEM. *P<0.05.

Full figure and legend (33K)

Experiment 3—interstimulus intervals

PPI exhibits temporal specificity in terms of the optimal interval between prepulse and pulse onsets. To determine whether the deficit in PPI in the KO mice reflected a shift in a timing function, we used a single prepulse intensity (73 dB, 8 dB above background) and a range of interstimulus intervals. A main effect of genotype (F[1,31]=13.71, P<0.001) indicated that, as expected, the PPI of the KO mice was severely disrupted (data not shown). An intensity-by-strain-by-gene interaction (F[6,186]=3.67, P<0.005) was also observed. Student–Newman–Keul analyses revealed that the KO mice exhibited impaired PPI (as compared to WT mice) at all interstimulus intervals examined. In addition, the 129SvPasIco mice exhibited significantly worse PPI than the C57BL/6 mice when the interval between the prepulse and the pulse was 300 ms or longer. As in schizophrenia patients,23 no shift from the 100 ms optimum was observed in the KO mice. Thus, the PPI deficit in mGluR5 KO mice is not due to an abnormality in the temporal function characteristic of PPI.

Experiment 4—equal startle

PPI is calculated for each animal using the startle magnitude values obtained on the STARTLE trials. It is therefore possible, despite the numerous reports of dissociations between PPI and startle magnitude (see eg Paylor and Crawley24), that the putative PPI deficit of the mGluR5 KO mice is in fact a reflection of their exaggerated startle magnitude. We therefore sought to equalize the startle magnitude of the responses of the WT and KO mice. To do so, we utilized the data from Experiment 2, determining the decibel level at which the startle response of the 129SvPasIco KO mice most closely resembled that of the 129SvPasIco WT mice to the 120-dB stimulus. As anticipated based on the design of the experiment, the mGluR5 WT and KO mice did not differ in their startle magnitude (F[1,15]<1; Figure 3). Nevertheless, the mGluR5 KO mice exhibited lower PPI than their WT counterparts (F[1,15]=10.60, P<0.01; Figure 3).

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

PPI with equal startle magnitudes. PPI values for WT and KO mice on a 129SvPasIco background. All mice received prepulses of 69, 73, and 77 dB. WT mice received pulses of 120 dB and KO mice received pulses of 105 dB. Startle magnitudes at these intensities are shown in the inset. White bars denote WT values, black bars denote KO values. Values are meansplusminusSEM. *P<0.05.

Full figure and legend (34K)

Experiment 5—multimodal

In schizophrenia, deficits are observed in both intramodal and cross-modal PPI.25 The studies presented above rely solely on acoustic stimuli. As such, the observed deficit might be due to an abnormality in auditory processing as opposed to sensorimotor gating. Accordingly, 129SvPasIco mice were tested with different modalities of prepulses and pulses. In addition to an acoustic prepulse (8 dB above background), a light prepulse was presented. Acoustic and tactile (airpuff) startle stimulus intensities were adjusted to produce similar startle magnitudes, which did not differ between WT and KO mice in this study (Figure 4). Again, the mGluR5 KO mice exhibited less acoustic–acoustic PPI (F[1,17]=5.80, P<0.05). Similar deficits in PPI were observed when an acoustic prepulse preceded a tactile pulse (F[1,17]= 10.34, P<0.005; Figure 4) and when a light prepulse preceded an acoustic pulse (F[1,17]=17.22, P<0.001). In the latter case, a negative mean value for PPI was observed, suggestive of prepulse facilitation, but this result cannot be considered facilitation due to the size of the error bars. When a light prepulse preceded a tactile pulse, not only was PPI highly variable, but the WT mice exhibited lower PPI than in the other modalities and the apparent deficit in the KO mice was not significant. Nevertheless, as in schizophrenia patients,25 the demonstration of deficient light-induced PPI confirms that the mGluR5 KO mice exhibit deficits in sensorimotor gating rather than hearing.

Figure 4.
Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Multimodal PPI. PPI values for mGluR5 WT and KO mice on a 129SvPasIco background using a variety of stimulus modalities for the pulse and the prepulse. Prepulse modalities are listed below the X-axis. Pulse modalities are listed below the prepulses. White bars denote WT values, black bars denote KO values. Values are meansplusminusSEM. *P<0.05.

Full figure and legend (43K)



The results from this battery of experiments lead us to conclude that mGluR5 KO mice, as hypothesized, exhibit a deficit in sensorimotor gating as reflected in reduced PPI. The decrease in PPI observed in the mGluR5 KO mice is not due to alteration in the startle threshold (Experiment 2) or startle magnitude (Experiment 4). Furthermore, as in schizophrenia,25,26 the decrease in PPI is observed across both multiple modalities (Experiment 5) and multiple prepulse intensities, and occurs at a range of interstimulus intervals (Experiment 3). The reduced PPI observed in the mGluR5 KO mice was not due to differences in reactivity to the prepulse stimuli, since none of the mice responded more to the prepulses than to the 65-dB background noise (Experiment 2). The PPI deficit of the mGluR5 KO mice is robust when the mutation is introduced into two different mouse strains (Experiment 1) and is replicable both within and across cohorts (data not shown). The combination of the results from this entire constellation of experiments allows us to state with confidence that the deficit observed in the mGluR5 KO mice is indeed a deficit in sensorimotor gating. In addition, our observation of a PPI deficit in mGluR5 KO mice is consistent with previously published abstracts27,28 as well as a recent report by Kinney et al29 that appeared after these studies were completed.

It should be noted, however, that the robustness of the PPI deficit of the mGluR5 KO mice appears to depend on which of the two currently available constructs for generating an mGluR5 KO is utilized.20,30 It has been observed28 that the PPI deficit of the mGluR5 KO mice generated in the lab of Dr François Conquet20 is more robust than that seen in the mice generated by Dr John Roder et al.30 Nevertheless, mGluR5 mice generated by both groups do exhibit deficits in PPI relative to their respective WTs (this report, Henry et al27,28 and Kinney et al29). The two groups backcrossed their respective mGluR5 KO mice onto different strains, one onto an outbred mouse strain,30 the other onto both C57BL/6 and 129SvPasIco, as reported here. Insofar as these background strains have been shown to vary widely in both startle magnitude and PPI levels,24 it is likely that the robustness of differences in startle and PPI due to deletion of mGluR5 is influenced by the background, as has been described for other phenotypes.31

In addition to the deficient PPI seen in both 129SvPasIco and C57BL/6 mGluR5 KO mice, the C57BL/6 mice, and to a lesser degree the 129SvPasIco mice, exhibited increases in startle magnitude. While the hyper-reactivity in the C57BL/6 mice was very striking, the 129SvPasIco mGluR5 KO mice exhibited a less pronounced exaggeration in startle magnitude than the C57BL/6 mGluR5 KO mice. Indeed, when small samples were involved, this increase in startle in the 129SvPasIco mGluR5 KO was not always statistically significant and was not evident with tactile stimuli (eg Experiment 5). Both the mGluR5 WT and the mGluR5 KO mice of both strains exhibited significant startle responses at the same dB level (85–90 dB), indicating no shift in the threshold for startle in the KO mice. To verify that the effects of the 129SvPasIco mGluR5 KO on startle magnitude could be dissociated from the effects on PPI, startle magnitude was held constant across groups (through the use of different startle stimulus intensities, one of 105 dB and one of 120 dB), and PPI measured under these conditions. The fact that the mGluR5 KO mice exhibited impaired PPI compared to their WT counterparts while concurrently exhibiting comparable startle magnitude strongly suggests both that the two measures are dissociable, as reported by others (eg Paylor and Crawley24), and that the deficit of the mGluR5 KO mice is not due to an alteration in startle magnitude or startle thresholds.

Although the similar startle thresholds implies that the WT and KO mice did not differ in hearing sensitivity, hearing deficits could still influence PPI. Indeed, C57BL/6 mice have been shown to exhibit high-frequency hearing loss beginning as early as 3 months old (eg Willot32). The broadband stimulus utilized in these studies minimizes the impact of selective high-frequency hearing loss. Furthermore, we elicited PPI using a variety of sensory modalities for both the prepulses and the pulses and found that the mGluR5 KO mice exhibited deficient PPI independently of the modality of stimulation.

The present findings of deficient PPI in mGluR5 KO mice are consistent with both human and rodent literature suggesting a contribution of mGluR5 to the etiology or treatment of schizophrenia or related psychiatric disorders that are characterized by deficits in sensorimotor gating. Pharmacological studies have shown that a metabotropic glutamate mixed Group I/II agonist injected directly into the nucleus accumbens or the striatum produces a PPI deficit.33 Systemic administration of the more specific Group II mGluR2/3 agonist LY314582, or its racemate (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740)34 did not alter PPI alone nor did it alter the effects of the NMDA antagonist PCP.35,36 In contrast, while the mGluR5 antagonist MPEP had no effect on PPI by itself even when administered at doses reported to attain at least 90% receptor occupancy,29,36,37,38 it was shown to exacerbate the PPI deficit produced by PCP administration.29,36 Thus, although MPEP alone does not appear to disrupt PPI in rodents, the influence of this mGluR5 antagonist on PPI in PCP-treated animals is consistent with the phenotypic difference in PPI in the mGluR5 KO mice. Furthermore, administration of an mGluR5 agonist reversed the PPI deficit induced by administration of amphetamine.29 An mGluR5 agonist therefore has the anticipated opposite effect of an antagonist or other manipulation resulting in the unavailability of the mGlu5 receptors. Taken together, these pharmacological studies point towards a role of the Group I mGluRs, and more specifically, mGluR5 in the modulation of PPI.

The pharmacological data from the rodents are consistent with data from patients with schizophrenia in implicating a role of mGluR5 in the etiology or treatment of this disease. Just as drug administration produces changes in levels of available mGlu5 receptors in rodent brains, so too does schizophrenia in the human brain. In fact, several changes in glutamatergic markers have been noted in the brains of schizophrenia patients. Among these alterations in glutamatergic markers is an increase in neuronal mGluR5 found in the pyramidal layers of area 11 in prefrontal cortex of schizophrenia patients.17 In addition, gene linkage studies have also implicated the mGluR5 gene on chromosome 11 as being abnormal in schizophrenia.18 This abnormality of the mGluR5 gene in schizophrenia may be functionally similar to the absence of this gene in the mGlu5 KO mice and may partially explain why mice missing the mGluR5 gene exhibit PPI deficits such as those seen in patients with schizophrenia. We therefore believe that the work presented here indicates an important role for mGluR5 in the modulation of sensorimotor gating and perhaps even the etiology of schizophrenia, a psychiatric disorder associated with a deficit in PPI.



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SAB was supported by MH12961. SCD was supported by MH12249. This work was supported by DA02925 and MH42228 to MAG. MAG holds an equity interest in San Diego Instruments.



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Resolving schizophrenia's CATCH22

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