Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons

Abstract

SummaryAbnormalities in prefrontal GABAergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to maternal immune activation, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders.

Dominant-Negative DISC1 Alters the Dopaminergic Modulation of Inhibitory Interneurons in the Mouse Prefrontal Cortex

“…While some neurons still showed an increase in firing in response to quinpirole, most FS interneurons failed to increase their firing. This observation is consistent with what has been found in many different animal manipulations that yielded abnormal interneuron activity in the PFC, such as the neonatal ventral hippocampal lesion model [64], rats treated in utero with methylazoxymethanol acetate [14, 70], and maternal immune activation [71], among others. These models disrupt the normal developmental trajectory of inhibitory circuits.…”

Development of large-scale functional networks from birth to adulthood: A guide to the neuroimaging literature

“…It is also clear that several prenatal factors (e.g. immune and endocrine systems) strongly affect postnatal network trajectories (Canetta et al, 2016; Scheinost et al, 2016b). Future work examining node participation coefficients in functional networks and other centrality measures in structural networks (see network measures ) promises to shed greater light on the emergence of network integrators and their potential susceptibility to pre- and post-natal factors.…”

Tumour necrosis factor-mediated homeostatic synaptic plasticity in behavioural models: testing a role in maternal immune activation

“…Our goal here was to evaluate the role of TNF-mediated regulation of circuit function during inflammatory neurodevelopment conditions, using the MIA model of neuropsychiatric disorders. We saw no differential MIA-induced behavioural deficits in TNF 2/2 mice compared with WT mice, and conclude that [74,81,84], the genetic background of mice plays a large role in the behavioural outcome of MIA [52], particularly for anxiety-related phenotypes [84]. Specifically, MIA was found to increase anxiety-like behaviour of offspring in NMRI mice but not in C57BL/6 J mice (as used here) [84].…”

“…We next compared the effect of MIA on the expression of anxiety-like behaviours in WT and TNF 2/2 mice, which typically is increased in adult offspring from immune-stimulated mothers [81,84]. We observed no significant differences in baseline anxiolytic behaviour between saline and TNF 2/2 mice in any of the measurements, looking at time or frequency in the different zones of the EPM ( figure 2c-f).…”

“…Further, maternal immune activation increases limbic expression of GABA receptors, which correlates with observed decreased exploratory behaviour [80]. MIA also results in decreased GABAergic transmission in the medial prefrontal cortex [81]. Here, we tested the contribution of TNF to the MIAinduced behavioural changes in social approach and the EPM.…”