Prenatal stress delays inhibitory neuron progenitor migration in the developing neocortex
Introduction
Research on the effects of prenatal stress increasingly demonstrates that this adverse life event can be a significant risk factor for neuropsychiatric disorders. Stress in pregnant women has significant effects on fetal physiology (Monk et al., 2004, Wadhwa, 2005). Prenatal stress has also been linked to childhood behavioral, physiological, and emotional problems (Huot et al., 2004, Martini et al., 2010, O’Connor et al., 2003). Perinatal stressors have an association with symptom severity in Tourette syndrome (Leckman et al., 1990) and with autistic-like symptoms (Ronald et al., 2010). Psychiatric problems that develop in adolescence and young adulthood may also be related to maternal stress during pregnancy. Obstetric complications are more frequent in the maternal history of patients with bipolar disorder (Kinney et al., 1998). Furthermore, the development of schizophrenia has been shown to be correlated with stress experienced during pregnancy (review: King et al., 2005). Changes in the brain occurring during prenatal stress must have long lasting consequences in order to explain the emergence of psychiatric illness years later. The mechanisms by which persistent cellular changes may be induced in the developing fetus by maternal stress are not understood.
Many of the neuropsychiatric disorders correlated with prenatal stress implicate the GABAergic system. Schizophrenia has been shown to be associated with a loss of GABAergic neurons in the hippocampus and neocortex and a change in their functioning, particularly those expressing parvalbumin and somatostatin (Hashimoto et al., 2008, Reynolds et al., 2004, Benes, 1999, Benes and Berretta, 2001). GABAergic abnormalities have also been implicated in the pathogenesis of autism and Tourette syndrome (Kataoka et al., 2010, Yip et al., 2008). The mechanisms by which these potentially critical changes in adult GABA neurons occur are not understood.
There are some data to suggest that prenatal stress and associated high levels of corticosteroids during embryonic development lead to changes in GABAergic populations in the adult brain which may reveal general pathological mechanisms involved in psychiatric disorders. Rat offspring of “stressed” mothers have fewer benzodiazepine binding sites in the amygdala and hippocampus, less GABA/benzodiazepine inhibitory activity and more sensitivity of GAD65 expression in these same regions in response to later corticosterone exposure (Barros et al., 2006, Stone et al., 2001, Weinstock, 1997). GABAergic synapses in the hypothalamus, as measured by vGAT immunocytochemistry, have also been shown to be increased (Viltart et al., 2006). Prenatal stress lowers the seizure threshold in the dorsal hippocampus (Edwards et al., 2002), suggesting a loss of inhibition of this region.
These results reflect changes in the adult population of GABAergic neurons following exposure to prenatal stress during critical periods of inhibitory neuron development. In rodents, GABAergic neurogenesis begins in the ganglionic eminence of the ventral telencephalon midway through embryonic development (∼embryonic day 10–11) and continues for approximately a week (Fig. 1A; for review see Corbin and Butt, 2011). GABaergic interneuron progenitors destined for the hippocampus and neocortex migrate away from the ventricular zone of the ventral telencephalon and tangentially move into the developing cortical plate in two migratory streams within the marginal zone and intermediate zone. After moving tangentially, GABAergic progenitors radially migrate and integrate into different cortical layers, a process that begins in lateral regions within 3 days of inhibitory neuron birth. Most migration is completed by birth. It is unknown what impact prenatal stress has on GABAergic progenitors that may result in abnormalities in the resulting mature neurons within adult brain networks. Some evidence for the impact of stress on GABAergic systems comes from studies in early postnatal life and adulthood in which acute and chronic stress leads to reductions in GABA signaling (review: Luscher et al., 2011). However, GABAergic developmental events on which stress could impinge are significantly different in prenatal vs postnatal periods.
Prenatal stress has also been discussed as a potential major influence on neuronal migration (Schneider et al., 2002) and gestational dexamethasone treatment has been demonstrated to have an impact on migration via an actin regulatory protein, caldesmon (Fukumoto et al., 2009). Given this framework, we examined the development of precursors to inhibitory neurons in the prenatally stressed telencephalon using GAD67GFP knock-in mice (Tamamaki et al., 2003) which consistently label GABAergic progenitors in the embryonic brain. GFP-labeled interneuron progenitor populations within the ganglionic eminence and dorsal telencephalon were evaluated at multiple embryonic time points following prenatal stress. Beginning one day after the start of prenatal stress, both the proliferation and different phases of migration of these GABAergic neuron progenitors were evaluated to assess the impact of prenatal stress.
Section snippets
Mice
GAD67-GFP(Δneo) mice (Tamamaki et al., 2003) were bred on a CD1 background. GAD67GFP+/− male mice were used for mating with CD1 females lacking the GAD67GFP knock-in gene. Timed pregnancies were monitored following detection of vaginal plug on embryonic day 0 (E0) and thirty pregnant females were singly housed from E12. All experimental procedures involving animals were performed in accordance with the Yale Animal Resources Center and Institutional Animal Care and Use Committee (IACUC) policies.
Distribution of GABAergic cells
In order to assess GABAergic progenitor populations during their proliferation and migration, we examined the GAD67GFP+ cells in three ways: (1) density within the ventral telencephalon (their birthplace and initial migrating zone), and the dorsal telencephalon (their target zone) (Fig. 1A); (2) their circumferential distribution in their migratory paths tangentially around the dorsal telencephalon (Fig. 1A); and (3) their radial distribution as they integrate into the cortical plate after the
Discussion
Here we demonstrate that a well-validated model of prenatal stress in mice resulted in changes in the distribution of GAD67GFP+ GABAergic cells within the dorsal telencephalon of the offspring that support a model in which stress impairs the migration of GABAergic progenitors and their subsequent integration in the cerebral cortex. This change in the migration of GABAergic progenitors began after only one day of stress and was still observable after the last day of stress. In addition, there
Conclusions
The effects of prenatal stress on inhibitory neuron precursor migration may demonstrate one component of the developmental pathophysiology of stress-related behavioral problems. Alterations in the migration of embryonic neuronal precursors may arise from environmental influences, genetic variation or the interaction of these two. One gene implicated in trait anxiety, MAMDC1 or MDGA1, is involved in neuronal migration (van den Oord et al., 2008, Takeuchi and O’Leary, 2006) suggesting that a
Role of the funding sources
This work was supported by National Institutes Health Grants K08 MH086812-01 (HES), T32 MH018268 (HES), R25 MH071584 (HES), R25 MH077823 (HES), and R01 MH067715 (FV), the Harris Professorship fund (FV), Brain and Behavior Research Foundation NARSAD Young Investigator Award from the Mortimer D. Sackler Psychobiology Program (HES), American Academy of Child and Adolescent Psychiatry Pilot Research Award (HES), and an American Psychiatric Institute for Research and Education/Wyeth Pharmaceuticals
Conflicts of interest
None declared.
Acknowledgments
We would like to acknowledge Rachael Couture, Sonia Lombroso, Idil Yazgan, and Shawna Ellis for technical assistance and members of the Vaccarino lab for helpful discussion. This work was supported by National Institutes Health Grants K08 MH086812 (HES), T32 MH018268 (HES), R25 MH071584 (HES), R25 MH077823 (HES), and R01 MH067715 (FV), the Harris Professorship fund (FV), Brain and Behavior Research Foundation NARSAD Young Investigator Award from the Mortimer D. Sackler Psychobiology Program
References (55)
Evidence for altered trisynaptic circuitry in schizophrenic hippocampus
Biol. Psychiatry
(1999)- et al.
GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder
Neuropsychopharmacology
(2001) - et al.
Maternal stress during pregnancy predicts cognitive ability and fearfulness in infancy
J. Am. Acad. Child Adolesc. Psychiatry
(2007) - et al.
The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes
Neuron
(2008) - et al.
Dlx transcription factors promote migration through repression of axon and dendrite growth
Neuron
(2007) - et al.
Prenatal stress alters seizure thresholds and the development of kindled seizures in infant and adult rats
Horm. Behav.
(2002) - et al.
Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1
Neuron
(2004) - et al.
The effects of prenatal stress on the development of hypothalamic paraventricular neurons in fetal rats
Neuroscience
(1999) - et al.
Ventromedian forebrain dysgenesis follows early prenatal ethanol exposure in mice
Neurotoxicol. Teratol.
(2011) - et al.
Perinatal factors in the expression of Tourette's syndrome: an exploratory study
J. Am. Acad. Child Adolesc. Psychiatry
(1990)
Postnatal stimulation of the pups counteracts prenatal stress-induced deficits in hippocampal neurogenesis
Biol. Psychiatry
Anxiety disorders before birth and self-perceived distress during pregnancy: associations with maternal depression and obstetric, neonatal and early childhood outcomes
Early Hum. Dev.
Fetal heart rate reactivity differs by women's psychiatric status: an early marker for developmental risk?
J. Am. Acad. Child Adolesc. Psychiatry
Postmitotic Nkx2-1 controls the migration of telencephalic interneurons by direct repression of guidance receptors
Neuron
Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response
Brain Behav. Immun.
The impact of prenatal stress, fetal alcohol exposure, or both on development: perspectives from a primate model
Psychoneuroendocrinology
The effects of prenatal stress on the Purkinje cell neurogenesis
Neurotoxicol. Teratol.
Prenatal stress and neonatal rat brain development
Neuroscience
Prenatal stress alters Fos protein expression in hippocampus and locus coeruleus stress-related brain structures
Psychoneuroendocrinology
Psychoneuroendocrine processes in human pregnancy influence fetal development and health
Psychoneuroendocrinology
Does prenatal stress impair coping and regulation of hypothalamic-pituitary-adrenal axis?
Neurosci. Biobehav. Rev.
Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes
Science
Prenatal stress and early adoption effects on benzodiazepine receptors and anxiogenic behavior in the adult rat brain
Synapse
Arx is a direct target of Dlx2 and thereby contributes to the tangential migration of GABAergic interneurons
J. Neurosci.
Developmental mechanisms for the generation of telencephalic interneurons
Dev. Neurobiol.
Ambient GABA promotes cortical entry of tangentially migrating cells derived from the medial ganglionic eminence
Cereb. Cortex
The timing of prenatal exposure to maternal cortisol and psychosocial stress is associated with human infant cognitive development
Child Dev.
Cited by (69)
Impact of stress on inhibitory neuronal circuits, our tribute to Bruce McEwen
2022, Neurobiology of StressThe impact of (ab)normal maternal environment on cortical development
2021, Progress in NeurobiologyPrenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder: focus on biological pathways and epigenetic mechanisms
2020, Neuroscience and Biobehavioral ReviewsPrenatal stress: Effects on fetal and child brain development
2020, International Review of NeurobiologyCitation Excerpt :Some of the neurodevelopmental changes associated with prenatal stress could be counteracted by the postnatal environment (Morley-Fletcher, Rea, Maccari, & Laviola, 2003). Several of the animal studies of the effects of prenatal stress on the offspring have also studied brain structure (Petit et al., 2015; Stevens, Su, Yanagawa, & Vaccarino, 2013) and connectivity (Goelman, Ilinca, Zohar, & Weinstock, 2014) and found changes similar to those observed in humans. Changes in the developmental trajectory of limbic/paralimbic brain regions central to attention/cognitive processing and emotional/social behavior, including the hippocampus and amygdala have been described (Kraszpulski, Dickerson, & Salm, 2006; Monk et al., 2019).
Purinergic signalling and brain development
2019, Seminars in Cell and Developmental BiologyCellular stress mechanisms of prenatal maternal stress: Heat shock factors and oxidative stress
2019, Neuroscience LettersCitation Excerpt :GABAergic progenitors differentiate into interneurons as they migrate and integrate into the neocortex, ultimately forming the inhibitory neural circuitry required for cognition, learning, and motor tasks [7,56]. Prenatal stress late in mouse gestation reduces GABAergic progenitor production [190], while prenatal stress early in gestation delays the tangential migration in GABAergic interneurons [180]. Multiple components of the maternal physiologic stress response have effects on GABAergic neuron development.