Infections in Pregnancy and GABA Neuron Development
Intra-uterine infections may impair development of fetal GABAergic neurons.
Posted Feb 28, 2021 | Reviewed by Kaja Perina
It goes without saying that the health of a pregnant mother and the conditions inside the womb play a vital role in the development of a fetus. In addition to requiring an optimal environment with adequate nutrition, oxygen, and blood supply, conversely, the fetus, if exposed to toxins, hormonal imbalances, or inflammatory states, is at risk for a wide array of conditions once they enter the world. Psychiatric conditions are no exception.
While familial inheritance is well-known, it has also been well-established that psychiatric conditions can be passed onto offspring via exposure in utero to infections. For instance, some individuals who had prenatal exposure to influenza virus went on to develop major affective disorder (Machon, Mednick, & Huttenen, 1997). Moreover, prenatal exposure to rubella virus has been significantly associated with subsequent cognitive impairment later in life, and also, to a lesser extent, with schizophrenia (Brown et al., 2001). Even herpes simplex exposure has been associated with psychoses in adult offspring (Buka et al., 2008).
So what is the underlying mechanism at play with these in utero infections and subsequent psychiatric conditions in offspring? Well, recent findings in a study of mice by a team in Denmark suggest that infection may affect the development of neurons, particularly GABAergic interneurons, at multiple steps depending on the stage of typical brain development at which infection is present and has its effect (Vasistha et al., 2019).
The authors sought to build on findings in prior literature that immune activation in pregnant mother affected the balance of excitatory and inhibitory neurons, particularly the latter, and specifically, led to abnormalities in the function of GABAergic neurons (Canetta et al., 2016).
The authors recreated the condition of a viral infection in a mouse model, whereby they injected a synthetic mimic of viral, double-stranded RNA into pregnant mice and monitored the development of GABAergic interneurons in the fetal mice. What the authors found was that infections, and the subsequent activation of the maternal immune system, targeted and compromised several steps at different points of the development of cortical GABAergic interneurons. These include the generation, proliferation, and migration of neuronal precursor cells, as well as their subsequent maturation into functioning neurons. This had an effect on overall morphology of the brains of these offspring mice, such as fewer neurons in general, and changes in the overall distribution in regions of the cortex.
This did, in fact, have a symptomatic manifestation in the mice once they were born. These offspring exhibited cognitive decline and impaired social interactions. What was also observed was a decrease in prepulse inhibition. In case you’re unfamiliar with what prepulse inhibition is, it is the phenomenon in which there is an expected decrease in a startle response when a stimulus of low intensity is administered before a more intense stimulus. In these mice, there was less of this prepulse inhibition, and more of a persistent startle response.
These findings are all symptoms typically associated with psychiatric conditions. Cognitive and social impairment are seen with a myriad of conditions such as schizophrenia, autism spectrum disorders, and personality disorders. Decreased prepulse inhibition is something you would expect with anxiety and panic disorders.
Just as important is the fact that the particular effect of infections depends on the time of insult. Therefore, the stage of fetal brain development at which the fetal mice were exposed to the viral mimic dictated and matched the particular biological process in the cortex that was dysfunctional in this mice. This may account for the great variation in the phenotypes of brain function compromise in affected offspring.
The notion of impaired inhibitory neuronal development is definitely intuitive, particularly with respect to schizophrenia, which has been associated with compromised GABAergic function, and resultant positive symptoms. (Gonzalez-Burgos, Hashimoto, & Lewis, 2010). It is definitely plausible that infections in utero are one such form of insult that can impair the development of these neurons and lead to a psychiatric condition like schizophrenia. One could further postulate that, since there are a spectrum of psychotic disorders, then perhaps the time of infection in utero could determine which condition on the spectrum, whether it be schizophrenia or schizoaffective disorder, would be acquired by the offspring.
It would be interesting to see how other psychiatric conditions are linked to infections in utero, which particular types of neuronal cell(s) is/are affected, and what the particular biological mechanisms underpinning the pathology of these conditions are. Only further research and longitudinal cohort studies with actual psychiatry patients will elucidate this further.
In any case, these findings are very insightful, and highlight just how vital it is, for the fetus’ sake, for a pregnant woman and her health care providers to be on their toes in ensuring that the woman is healthy and free from any stressors that could otherwise go on to have dire health ramifications for her child or children.
Buka, S. L., Cannon, T. D., Torrey, E. F., Yolken, R. H., & Collaborative Study Group on the Perinatal Origins of Severe Psychiatric Disorders. (2008). Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring. Biological psychiatry, 63(8), 809-815.
Brown, A. S., Cohen, P., Harkavy-Friedman, J., Babulas, V., Malaspina, D., Gorman, J. M., & Susser, E. S. (2001). Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biological psychiatry, 49(6), 473-486.
Canetta, S., Bolkan, S., Padilla-Coreano, N., Song, L., Sahn, R., Harrison, N. L., ... & Kellendonk, C. (2016). Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons. Molecular psychiatry, 21(7), 956.
Gonzalez-Burgos, G., Hashimoto, T., & Lewis, D. A. (2010). Alterations of cortical GABA neurons and network oscillations in schizophrenia. Current psychiatry reports, 12(4), 335–344. doi:10.1007/s11920-010-0124-8
Machon, R. A., Mednick, S. A., & Huttunen, M. O. (1997). Adult major affective disorder after prenatal exposure to an influenza epidemic. Archives of general psychiatry, 54(4), 322-328.
Vasistha, N. A., Pardo-Navarro, M., Gasthaus, J., Weijers, D., Müller, M. K., García-González, D., ... & Hougaard, K. S. (2019). Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner. Molecular psychiatry, 1-17.