Maternal Immune Activation Induces Cortical Catecholaminergic Hypofunction and Cognitive Impairments in Offspring

Abstract

Background Impairment of specific cognitive domains in schizophrenia has been associated with prefrontal cortex (PFC) catecholaminergic deficits. Among other factors, prenatal exposure to infections represents an environmental risk factor for schizophrenia development in adulthood. However, it remains largely unknown whether the prenatal infection-induced changes in the brain may be associated with concrete switches in a particular neurochemical circuit, and therefore, if they could alter behavioral functions. Methods In vitro and in vivo neurochemical evaluation of the PFC catecholaminergic systems was performed in offspring from mice undergoing maternal immune activation (MIA). The cognitive status was also evaluated. Prenatal viral infection was mimicked by polyriboinosinic-polyribocytidylic acid (poly(I:C)) administration to pregnant dams (7.5 mg/kg i.p., gestational day 9.5) and consequences were evaluated in adult offspring. Results MIA-treated offspring showed disrupted recognition memory in the novel object recognition task (t = 2.30, p = 0.031). This poly(I:C)-based group displayed decreased extracellular dopamine (DA) concentrations compared to controls (t = 3.17, p = 0.0068). Potassium-evoked release of DA and noradrenaline (NA) were impaired in the poly(I:C) group (DA: Ft[10,90] = 43.33, p < 0.0001; Ftr[1,90] = 1.224, p = 0.2972; Fi[10,90] = 5.916, p < 0.0001; n = 11); (NA: Ft[10,90] = 36.27, p < 0.0001; Ftr[1,90] = 1.841, p = 0.208; Fi[10,90] = 8.686, p < 0.0001; n = 11). In the same way, amphetamine‐evoked release of DA and NA were also impaired in the poly(I:C) group (DA: Ft[8,328] = 22.01, p < 0.0001; Ftr[1,328] = 4.507, p = 0.040; Fi[8,328] = 2.319, p = 0.020; n = 43); (NA: Ft[8,328] = 52.07; p < 0.0001; Ftr[1,328] = 4.322; p = 0.044; Fi[8,398] = 5.727; p < 0.0001; n = 43). This catecholamine imbalance was accompanied by increased dopamine D1 and D2 receptor expression (t = 2.64, p = 0.011 and t = 3.55, p = 0.0009; respectively), whereas tyrosine hydroxylase, DA and NA tissue content, DA and NA transporter (DAT/NET) expression and function were unaltered. Conclusions MIA induces in offspring a presynaptic catecholaminergic hypofunction in PFC with cognitive impairment. This poly(I:C)-based model reproduces catecholamine phenotypes reported in schizophrenia and represents an opportunity for the study of cognitive impairment associated to this disorder.

Transcriptional and Cellular Response of hiPSC-derived Microglia-Neural Progenitor Co-Cultures Exposed to IL-6

“…For example, recent evidence suggests the immortalised human dopaminergic neuronal precursor cell line LUHMES (Lotharius et al, 2002) expresses low levels of IL6R, albeit very low compared to microglia (Nishi et al, 2023). Furthermore, there are several reports in the literature on the effects of MIA in rodent models using TLR3 agonists on midbrain dopamine neuron development in vivo, which are associated with behavioural effects and impaired cortical function (Meyer et al, 2008;Vuillermot et al, 2010;Luchicchi et al, 2016;Purves-Tyson et al, 2021;Perez-Palomar et al, 2023). Therefore, we suggest our 2D hiPSC-derived forebrain co-culture model offers a simplistic, reproducible and scalable model that we can use to test hypotheses that NPCs with different regional origins, for example forebrain and midbrain, may show differential responses to IL-6 as a result.…”

Impact of respiratory viral infections during pregnancy on the neurological outcomes of the newborn: current knowledge

“…A recent study conducted by Perez-Palomar and colleagues in a rodent model proved that MIA disrupts dopaminergic and noradrenergic pathways in the prefrontal cortex, affecting cognitive behavior in offspring. These circuitries are notably impaired in schizophrenia ( Perez-Palomar et al, 2023 ).…”