Molecular Psychiatry (2002) 7, 609–616  2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus M Roceri 1,3 , W Hendriks 2 , G Racagni 1,3 , BA Ellenbroek 2 and MA Riva 1 1 Center of Neuropharmacology, Department of Pharmacological Sciences and Center of Excellence for Neurodegenerative Disorders, University of Milan, Milan, Italy; 2 Department of Psychoneuropharmacology, University of Nijmegen, Nijmegen, The Netherlands; 3 IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, Italy It is well accepted that events that interfere with the normal program of neuronal differentiation and brain maturation may be relevant for the etiology of psychiatric disorders, setting the stage for synaptic disorganization that becomes functional later in life. In order to investigate molecular determinants for these events, we examined the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) and the glutamate NMDA receptor following 24 h maternal separation (MD) on postnatal day 9. We found that in adulthood the expression of BDNF as well as of NR-2A and NR-2B, two NMDA receptor forming subunits, were significantly reduced in the hippocampus of MD rats whereas, among other structures, a slight reduction of NR-2A and 2B was detected only in prefrontal cortex. These changes were not observed acutely, nor in pre-weaning animals. Furthermore we found that in MD rats the modulation of hippocampal BDNF in response to an acute stress was altered, indicating a persistent func- tional impairment in its regulation, which may subserve a specific role for coping with chal- lenging situations. We propose that adverse events taking place during brain maturation can modulate the expression of molecular players of cellular plasticity within selected brain regions, thus contributing to permanent alterations in brain function, which might ultimately lead to an increased vulnerability for psychiatric diseases. Molecular Psychiatry (2002) 7, 609–616. doi:10.1038/sj.mp.4001036 Keywords: animal model; brain-derived neurotrophic factor; glutamate; neurodevelopment; schizo- phrenia; stress Introduction It has been long realized that experiences taking place early in life have a profound influence on brain devel- opment, produce persistent effects on its function while determining individual differences in the vul- nerability to stress. 1,2 Early work by Levine has clearly demonstrated that stimulation of neonatal rats affects their endocrine and behavioral responses later in life. 3 While brief, repeated manipulations (handling) may be beneficial in terms of stress reactivity and result in a more efficient coping with the environment, longer separations appear detrimental. 4–6 Accordingly adverse life events during the perinatal period produce perma- nent alterations at the level of hypothalamic-pituitary- adrenal (HPA) axis, which are accompanied by high anxiety-like behavior and age-related memory impair- ment. 7–9 Furthermore early adverse situations may increase the vulnerability to psychiatric disorders, Correspondence: MA Riva, Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. E-mail: marivamailserver. unimi.it Received 25 July 2001; revised 16 October 2001; accepted 14 November 2001 such as depression and schizophrenia that, to some extent, can be characterized by altered regulation of the HPA axis and abnormal responses to stress. 10,11 Hence if brain development is a key factor for disease susceptibility, the capability to reproduce alterations occurring early in life becomes crucial for animal modeling. Since mother–infant interaction may be a key factor for brain maturation and disease suscepti- bility, maternal deprivation (MD) represents a useful paradigm to study disturbances in brain function that might occur in response to adverse events during development. Specifically, we investigated short- and long-term molecular changes taking place after a single 24 h MD on postnatal day 9 (pnd-9), a paradigm that recapitu- lates several features of schizophrenia. 12 Although dif- ferent factors may be important for the derangement in brain development, we reasoned that early adverse life events could produce long-lasting impairment in brain function through changes in important modulators of synaptic plasticity. The present study tested this hypothesis through the analysis of the neurotrophin brain derived neurotrophic factor (BDNF) and the glut- amate N-methyl-D-aspartate (NMDA) receptor. Changes in neurotrophin levels as well as in the expression of this glutamate receptor subtype have