Elsevier

Biological Psychiatry

Volume 57, Issue 4, 15 February 2005, Pages 433-436
Biological Psychiatry

Brief reports
Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia

https://doi.org/10.1016/j.biopsych.2004.11.031Get rights and content

Background

Aberrant N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission has been implicated in schizophrenia. We studied whether transient inhibition of NMDA receptor activity during early postnatal development would produce a behavioral phenotype resembling that of individuals who are susceptible to develop schizophrenia.

Methods

Rat pups were given injections of the NMDA channel blocker MK801 on postnatal days 7 through 10. This period is akin to the prenatal second trimester of primate development. Cognitive function was tested in adulthood.

Results

Treatment with MK801 impaired cognitive flexibility and working memory. The impairment in cognitive flexibility was due to increased perseverative behavior. Treatment did not affect locomotor activity or recognition memory.

Conclusions

These results suggest that a brief disruption of NMDA receptors during a sensitive period of cortical development is sufficient to produce selective cognitive deficits that are relevant to schizophrenia.

Section snippets

Subjects and treatment schedule

Male Sprague-Dawley rats (n = 44) from 14 litters born to different dams (Harlan, Somerville, New Jersey) were used. On postnatal day 6 (P6), pups were randomly assigned to one of two treatment groups: vehicle (saline, 1 mL/kg) or MK801 (.1 mg/kg per injection). The pups were weighed daily from P6 through P11 and weekly thereafter.

Beginning on P7, pups received subcutaneous injections twice daily (09:00 and 16:00) for 4 days. Pups were removed from their dam for 1 hour for the injection, during

Results

MK801-treated pups gained significantly less weight during the treatment period than did their vehicle-treated counterparts (Table 1). However, by P60, there were no significant treatment-dependent differences.

Discussion

Transient inhibition of NMDA receptors during a period critical to frontal cortical development significantly impaired cognitive set-shifting abilities and working memory in adult rats without affecting long-term recognition memory or motor behavior. These results suggest that reducing NMDA receptor function during a critical period of development can produce selective cognitive deficits relevant to those reported in patients with schizophrenia and individuals who are susceptible to develop

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