- Email: [email protected]
Nothing Is Written in Stone
COMMENTARIES
Nothing Is Written in Stone Marian Joëls and E. Ronald de Kloet “
othing is written in stone,” the late Seymour Levine once said about the amazing plasticity of the developing brain in adaptation to an ever-changing environment (1). These adaptations, in response to environmental input, may cause lasting changes in the function of the evolutionary older brain circuitry, underlying emotion and cognition. As a result, adverse experiences in early life are thought to enhance disease vulnerability. However, recent evidence suggests that early adversity does not inevitably lead to a negative outcome (2). Rather, depending on genes and environmental context, early experience may program the brain for life to come. In this issue, Bagot et al. (3) describe the crucial role of the N-methyl-D-aspartate (NMDA) receptor in this programming effect. Bagot et al. recorded synaptic transmission in the dentate gyrus of adult rats that were raised by mothers spending either extremely high or low amounts of time licking and grooming (LG) their offspring during the first postnatal week (High vs. Low LG mothers, respectively). Earlier studies, particularly from the group of Michael Meaney, have shown that offspring from High compared with Low LG mothers show more complex hippocampal cells, more efficient long-term potentiation (LTP), better spatial learning, and more efficient release patterns of corticosterone after stress (2,4). Crossfostering could reverse some of these effects, emphasizing the relevance of early life environment rather than genetic background in the development of these phenotypes. Using this model, the present study shows that the ratio between NMDA and alphaamino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor–mediated currents in dentate granule cells is enhanced in Low compared with High LG offspring. Field potential recordings indicate that this is caused by enhanced transmission via NMDA receptors, whereas AMPA receptor function seems unchanged. In agreement, protein levels of NMDA receptor subunits are higher in Low than High LG offspring. In other words, an adverse early postnatal environment appears to upregulate NMDA transmission in the dentate gyrus over the long term. This finding comes as a bit of a surprise, because earlier studies have shown that NMDA receptor expression is decreased and LTP impaired in the adult offspring from Low compared with High LG mothers (5). The incongruity in NMDA receptor expression drives home the message that the proof of the pudding is in the recording: the only way to determine the functionality of receptors is by doing the actual electrophysiologic recordings. The second point—reduced LTP in light of enhanced NMDA receptor function—is experimentally addressed by the authors. They argue that the location of the NMDA receptors, that is, intra- versus extrasynaptic, is important and moreover that steady overstimulation of NMDA receptors may impair the ability to induce LTP. They confirm this view by showing that partial blockade of NMDA receptors in Low LG off-
N
From the Department of Neuroscience and Pharmacology (MJ), Rudolf Magnus Institute, University Medical Center Utrecht; and Department of Medical Pharmacology (ERdK), Leiden University Medical Center, The Netherlands. Address correspondence to Marian Joëls, Ph.D., Department of Neuroscience and Pharmacology, Division of Neuroscience, Rudolf Magnus Institute, University Medical Center Utrecht, PO Box 85500, 3508GA Utrecht, The Netherlands; E-mail: [email protected]. Received and accepted Jul 6, 2012.
0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2012.07.012
spring fully restores the ability to induce LTP, whereas this manipulation impairs LTP formation in High LG offspring. The data by Bagot et al. are convincing and raise a number of questions. First, how exactly is NMDA receptor function permanently upregulated in Low LG offspring? What are the essential mediators? Views on this matter may be derived from animal models in which the attachment of mother and pup was investigated either by scoring variations in maternal care, as done in the current study, or by separating mother and pups. It turned out that the hypothalamic-pituitary-adrenal axis in particular is crucial in translating environmental inputs into effects on the developing nervous system. The environment represents a strong epigenetic input that can completely override genetic predisposition. Prime examples are the enhanced expression of the vasopressin gene and suppressed expression of glucocorticoid receptors, which collectively program glucocorticoid resistance during stress as an important risk factor in later life (6). Interestingly, resistance to corticosterone is indeed what Bagot et al. observe when testing the NMDA function in low LG offspring. Recent findings by Sullivan et al. (7) indicate that programming effects imposed by stress mediators such as corticosterone, released by the pup during poor maternal care or neglect, are indeed important. They base their view on the observation that the olfactory system is highly activated in the presence of the mother to support attachment. Stressful environmental input drives a switch toward activation of the amygdala fear pathway, particularly during maternal absence, and this switch is operated by glucocorticoids. A second question relates to the relevance of these findings in rodents for cognitive function and eventually for psychopathology in humans. Given the crucial role of LTP in learning and memory formation, the reduced capacity to evoke LTP in Low compared with High LG offspring may provide a mechanistic basis for previous observations that early life adversity in rodents is linked to poor retention of contextual information, at least when tested under relatively nonstressful conditions (2). Yet in a highly stressful learning context, the rats with adverse early life conditions form strong memories, whereas those growing up under favorable conditions retain this information less efficiently. These findings in rodents suggest that early life environment may affect over time the functionality of important neurotransmitter systems such as the NMDA receptor and tailor it to an expected life to come. Malfunction of NMDA signaling on a more permanent basis may predispose to cognitive impairment under “normal” life conditions and inadequate interpretation of the environment, and this might add to the risk of acquiring psychopathology. Clearly, the genetic background in humans is much more variable than in the tested rat strain, and the rearing conditions of humans are far more complex. Nevertheless, even in humans, early life environment can exert a strong programming effect. A convincing example is the work of Tremblay et al. (8), who showed that high familial adversity can override genetic programming in monozygotic twins with respect to cortisol reactivity. Finally, are the present findings relevant for future strategies in ameliorating symptoms of, for example, depression? The article sheds some light on this by showing that corticosterone (and even corticosterone conjugated to albumin, a molecule that is unlikely to pass the plasma membrane) enhances NMDA receptor function within 20 minutes after being applied to slices from High LG rats. BIOL PSYCHIATRY 2012;72:432– 433 © 2012 Society of Biological Psychiatry
Commentary Such rapid effects of corticosterone, which differ from the classical genomic actions, are increasingly considered to be important for hippocampal function and are mediated in a complementary fashion by two receptor types: mineralocorticoid and glucocorticoid receptors. In adulthood, corticosterone rapidly enhances excitatory transmission in the dentate gyrus via mineralocorticoid receptors (9), whereas slower crosstalk of glucocorticoid receptors with the ERK1/2-MSK1-Elk-1 signaling can enhance histone-H3 acetylation in the nucleus of dentate cells (10). If such actions also take place early in life, low maternal care might boost NMDA receptor function in pups, an effect that could acquire a more permanent character through epigenetic programming, for example. Intervention by either various forms of tactile stimulation or blocking corticosterone action during this vulnerable period early in life could then be effective in preventing the NMDA system to grow out of control. Yet Bagot et al. show that even targeting the NMDA receptor in adulthood is highly effective, because downtuning its action by the antagonist (2R)-amino-5-phosphonovaleric acid restores the ability to induce LTP. The fact that in depressive patients, acute administration of the NMDA antagonist ketamine alleviates symptoms of treatment-resistant depression underpins the importance of understanding the pathways through which early life environment affects the function of the adult brain. Nothing is written in stone.
ERdK is on the scientific advisory board of Corcept Therapeutics and owns stock. MJ reports no biomedical financial interests or potential conflicts of interest.
BIOL PSYCHIATRY 2012;72:432– 433 433 1. Levine S (2005): Developmental determinants of sensitivity and resistance to stress. Psychoneuroendocrinology 30:939 –946. 2. Champagne DL, Bagot RC, vanHasselt F, Ramakers G, Meaney MJ, deKloet ER, et al. (2008): Maternal care and hippocampal plasticity: Evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J Neurosci 28:6037– 6045. 3. Bagot RC, Tse YC, Nguyen HB, Wong AS, Meaney MJ, Wong TP (2012): Maternal care influences hippocampal N-methyl-D-aspartate receptor function and dynamic regulation by corticosterone in adulthood. Biol Psychiatry 72:491– 498. 4. Liu D, Diorio J, Tannenbaum B, Francis D, Freedman A, Sharma S, et al. (1997): Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277:1659 –1662. 5. Bredy TW, Zhang TY, Grant RJ, Diorio J, Meaney MJ (2004): Peripubertal environmental enrichment reverses the effects of maternal care on hippocampal development and glutamate receptor subunit expression. Eur J Neurosci 20:1355–1362. 6. Murgatroyd C, Spengler D (2012): Genetic variation in the epigenetic machinery and mental health. Curr Psychiatry Rep 14:138 –149. 7. Moriceau S, Roth TL, Sullivan RM (2010): Rodent model of infant attachment learning and stress. Dev Psychobiol 52:651– 660. 8. Ouellet-Morin I, Boivin M, Dionne G, Lupien SJ, Arseneault L, Barr RG, et al. (2008): Variations in heritability of cortisol reactivity to stress as a function of early familial adversity among 19-month-old twins. Arch Gen Psychiatry 65:211–218. 9. Pasricha N, Joëls M, Karst H (2011): Rapid effects of corticosterone in the mouse dentate gyrus via a nongenomic pathway. J Neuroendocrinol 23:143–147. 10. Gutièrrez-Mecinas M, Trollope AF, Collins A, Morfett H, Hesketh SA, Kersanté F, et al. (2011): Long-lasting behavioral responses to stress involve a direct interaction of glucocorticoid receptors with ERK1/2MSK1-Elk-1 signaling. Proc Natl Acad Sci U S A 16:13806 –13811.
www.sobp.org/journal
Nothing Is Written in Stone Marian Joëls and E. Ronald de Kloet “
othing is written in stone,” the late Seymour Levine once said about the amazing plasticity of the developing brain in adaptation to an ever-changing environment (1). These adaptations, in response to environmental input, may cause lasting changes in the function of the evolutionary older brain circuitry, underlying emotion and cognition. As a result, adverse experiences in early life are thought to enhance disease vulnerability. However, recent evidence suggests that early adversity does not inevitably lead to a negative outcome (2). Rather, depending on genes and environmental context, early experience may program the brain for life to come. In this issue, Bagot et al. (3) describe the crucial role of the N-methyl-D-aspartate (NMDA) receptor in this programming effect. Bagot et al. recorded synaptic transmission in the dentate gyrus of adult rats that were raised by mothers spending either extremely high or low amounts of time licking and grooming (LG) their offspring during the first postnatal week (High vs. Low LG mothers, respectively). Earlier studies, particularly from the group of Michael Meaney, have shown that offspring from High compared with Low LG mothers show more complex hippocampal cells, more efficient long-term potentiation (LTP), better spatial learning, and more efficient release patterns of corticosterone after stress (2,4). Crossfostering could reverse some of these effects, emphasizing the relevance of early life environment rather than genetic background in the development of these phenotypes. Using this model, the present study shows that the ratio between NMDA and alphaamino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor–mediated currents in dentate granule cells is enhanced in Low compared with High LG offspring. Field potential recordings indicate that this is caused by enhanced transmission via NMDA receptors, whereas AMPA receptor function seems unchanged. In agreement, protein levels of NMDA receptor subunits are higher in Low than High LG offspring. In other words, an adverse early postnatal environment appears to upregulate NMDA transmission in the dentate gyrus over the long term. This finding comes as a bit of a surprise, because earlier studies have shown that NMDA receptor expression is decreased and LTP impaired in the adult offspring from Low compared with High LG mothers (5). The incongruity in NMDA receptor expression drives home the message that the proof of the pudding is in the recording: the only way to determine the functionality of receptors is by doing the actual electrophysiologic recordings. The second point—reduced LTP in light of enhanced NMDA receptor function—is experimentally addressed by the authors. They argue that the location of the NMDA receptors, that is, intra- versus extrasynaptic, is important and moreover that steady overstimulation of NMDA receptors may impair the ability to induce LTP. They confirm this view by showing that partial blockade of NMDA receptors in Low LG off-
N
From the Department of Neuroscience and Pharmacology (MJ), Rudolf Magnus Institute, University Medical Center Utrecht; and Department of Medical Pharmacology (ERdK), Leiden University Medical Center, The Netherlands. Address correspondence to Marian Joëls, Ph.D., Department of Neuroscience and Pharmacology, Division of Neuroscience, Rudolf Magnus Institute, University Medical Center Utrecht, PO Box 85500, 3508GA Utrecht, The Netherlands; E-mail: [email protected]. Received and accepted Jul 6, 2012.
0006-3223/$36.00 http://dx.doi.org/10.1016/j.biopsych.2012.07.012
spring fully restores the ability to induce LTP, whereas this manipulation impairs LTP formation in High LG offspring. The data by Bagot et al. are convincing and raise a number of questions. First, how exactly is NMDA receptor function permanently upregulated in Low LG offspring? What are the essential mediators? Views on this matter may be derived from animal models in which the attachment of mother and pup was investigated either by scoring variations in maternal care, as done in the current study, or by separating mother and pups. It turned out that the hypothalamic-pituitary-adrenal axis in particular is crucial in translating environmental inputs into effects on the developing nervous system. The environment represents a strong epigenetic input that can completely override genetic predisposition. Prime examples are the enhanced expression of the vasopressin gene and suppressed expression of glucocorticoid receptors, which collectively program glucocorticoid resistance during stress as an important risk factor in later life (6). Interestingly, resistance to corticosterone is indeed what Bagot et al. observe when testing the NMDA function in low LG offspring. Recent findings by Sullivan et al. (7) indicate that programming effects imposed by stress mediators such as corticosterone, released by the pup during poor maternal care or neglect, are indeed important. They base their view on the observation that the olfactory system is highly activated in the presence of the mother to support attachment. Stressful environmental input drives a switch toward activation of the amygdala fear pathway, particularly during maternal absence, and this switch is operated by glucocorticoids. A second question relates to the relevance of these findings in rodents for cognitive function and eventually for psychopathology in humans. Given the crucial role of LTP in learning and memory formation, the reduced capacity to evoke LTP in Low compared with High LG offspring may provide a mechanistic basis for previous observations that early life adversity in rodents is linked to poor retention of contextual information, at least when tested under relatively nonstressful conditions (2). Yet in a highly stressful learning context, the rats with adverse early life conditions form strong memories, whereas those growing up under favorable conditions retain this information less efficiently. These findings in rodents suggest that early life environment may affect over time the functionality of important neurotransmitter systems such as the NMDA receptor and tailor it to an expected life to come. Malfunction of NMDA signaling on a more permanent basis may predispose to cognitive impairment under “normal” life conditions and inadequate interpretation of the environment, and this might add to the risk of acquiring psychopathology. Clearly, the genetic background in humans is much more variable than in the tested rat strain, and the rearing conditions of humans are far more complex. Nevertheless, even in humans, early life environment can exert a strong programming effect. A convincing example is the work of Tremblay et al. (8), who showed that high familial adversity can override genetic programming in monozygotic twins with respect to cortisol reactivity. Finally, are the present findings relevant for future strategies in ameliorating symptoms of, for example, depression? The article sheds some light on this by showing that corticosterone (and even corticosterone conjugated to albumin, a molecule that is unlikely to pass the plasma membrane) enhances NMDA receptor function within 20 minutes after being applied to slices from High LG rats. BIOL PSYCHIATRY 2012;72:432– 433 © 2012 Society of Biological Psychiatry
Commentary Such rapid effects of corticosterone, which differ from the classical genomic actions, are increasingly considered to be important for hippocampal function and are mediated in a complementary fashion by two receptor types: mineralocorticoid and glucocorticoid receptors. In adulthood, corticosterone rapidly enhances excitatory transmission in the dentate gyrus via mineralocorticoid receptors (9), whereas slower crosstalk of glucocorticoid receptors with the ERK1/2-MSK1-Elk-1 signaling can enhance histone-H3 acetylation in the nucleus of dentate cells (10). If such actions also take place early in life, low maternal care might boost NMDA receptor function in pups, an effect that could acquire a more permanent character through epigenetic programming, for example. Intervention by either various forms of tactile stimulation or blocking corticosterone action during this vulnerable period early in life could then be effective in preventing the NMDA system to grow out of control. Yet Bagot et al. show that even targeting the NMDA receptor in adulthood is highly effective, because downtuning its action by the antagonist (2R)-amino-5-phosphonovaleric acid restores the ability to induce LTP. The fact that in depressive patients, acute administration of the NMDA antagonist ketamine alleviates symptoms of treatment-resistant depression underpins the importance of understanding the pathways through which early life environment affects the function of the adult brain. Nothing is written in stone.
ERdK is on the scientific advisory board of Corcept Therapeutics and owns stock. MJ reports no biomedical financial interests or potential conflicts of interest.
BIOL PSYCHIATRY 2012;72:432– 433 433 1. Levine S (2005): Developmental determinants of sensitivity and resistance to stress. Psychoneuroendocrinology 30:939 –946. 2. Champagne DL, Bagot RC, vanHasselt F, Ramakers G, Meaney MJ, deKloet ER, et al. (2008): Maternal care and hippocampal plasticity: Evidence for experience-dependent structural plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress. J Neurosci 28:6037– 6045. 3. Bagot RC, Tse YC, Nguyen HB, Wong AS, Meaney MJ, Wong TP (2012): Maternal care influences hippocampal N-methyl-D-aspartate receptor function and dynamic regulation by corticosterone in adulthood. Biol Psychiatry 72:491– 498. 4. Liu D, Diorio J, Tannenbaum B, Francis D, Freedman A, Sharma S, et al. (1997): Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277:1659 –1662. 5. Bredy TW, Zhang TY, Grant RJ, Diorio J, Meaney MJ (2004): Peripubertal environmental enrichment reverses the effects of maternal care on hippocampal development and glutamate receptor subunit expression. Eur J Neurosci 20:1355–1362. 6. Murgatroyd C, Spengler D (2012): Genetic variation in the epigenetic machinery and mental health. Curr Psychiatry Rep 14:138 –149. 7. Moriceau S, Roth TL, Sullivan RM (2010): Rodent model of infant attachment learning and stress. Dev Psychobiol 52:651– 660. 8. Ouellet-Morin I, Boivin M, Dionne G, Lupien SJ, Arseneault L, Barr RG, et al. (2008): Variations in heritability of cortisol reactivity to stress as a function of early familial adversity among 19-month-old twins. Arch Gen Psychiatry 65:211–218. 9. Pasricha N, Joëls M, Karst H (2011): Rapid effects of corticosterone in the mouse dentate gyrus via a nongenomic pathway. J Neuroendocrinol 23:143–147. 10. Gutièrrez-Mecinas M, Trollope AF, Collins A, Morfett H, Hesketh SA, Kersanté F, et al. (2011): Long-lasting behavioral responses to stress involve a direct interaction of glucocorticoid receptors with ERK1/2MSK1-Elk-1 signaling. Proc Natl Acad Sci U S A 16:13806 –13811.
www.sobp.org/journal