Maternal and Early Postnatal Immune Activation Produce Dissociable Effects on Neurotransmission in mPFC–Amygdala Circuits

Abstract

Inflammatory processes may be involved in the pathophysiology of neuropsychiatric illnesses including autism spectrum disorder (ASD). Evidence from studies in rodents indicates that immune activation during early development can produce core features of ASD (social interaction deficits, dysregulation of communication, increases in stereotyped behaviors, and anxiety), although the neural mechanisms of these effects are not thoroughly understood. We treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, or vehicle on gestational day 12.5 to produce maternal immune activation (MIA). Male offspring received either vehicle or lipopolysaccharide, which simulates a bacterial infection, on postnatal day 9 to produce postnatal immune activation (PIA). We then used optogenetics to address the possibility that early developmental immune activation causes persistent alterations in the flow of signals within the mPFC to basolateral amygdala (BLA) pathway, a circuit implicated in ASD. We found that our MIA regimen produced increases in synaptic strength in glutamatergic projections from the mPFC to the BLA. In contrast, our PIA regimen produced decreases in feedforward GABAergic inhibitory postsynaptic responses resulting from activation of local circuit interneurons in the BLA by mPFC-originating fibers. Both effects were seen together when the regimens were combined. Changes in the balance between excitation and inhibition were differentially translated into the modified spike output of BLA neurons. Our findings raise the possibility that prenatal and postnatal immune activation may affect different cellular targets within brain circuits that regulate some of the core behavioral signs of conditions such as ASD. Immune system activation during prenatal and early postnatal development may contribute to the development of autism spectrum disorder (ASD). Combining optogenetic approaches and behavioral assays that reflect core features of ASD (anxiety, decreased social interactions), we uncovered mechanisms by which the ASD-associated behavioral impairments induced by immune activation could be mediated at the level of interactions within brain circuits implicated in control of emotion and motivation (mPFC and BLA, specifically). Here, we present evidence that prenatal and postnatal immune activation can have different cellular targets in the brain, providing support to the notion that the etiology of ASD may be linked to the excitation/inhibition imbalance in the brain affecting the signal flow within relevant behavior-driving neural microcircuits.

The GABA Developmental Shift Is Abolished by Maternal Immune Activation Already at Birth

“…In mature dentate granule cells recorded after MIA, intrinsic properties are altered and the frequency of miniature inhibitory postsynaptic currents (mIPSCs) is reduced (Zhang and van Praag 2015). Increased sEPSCs amplitude has also been reported in neurons of the basolateral amygdala in MIA mice (Li et al 2018). Thus, in utero exposure to MIA disrupts the inhibitory/excitatory balance from birth and into adulthood.…”

Mast Cells, Stress, Fear and Autism Spectrum Disorder

“…Evidence from rodents supports the possibility that environment-stress interactions trigger inflammation and affect brain regions that govern the "fear response" [202][203][204][205]. Prenatal stress was reported to decrease neuron excitability in the amygdala and social behavior in rats [206].…”

Sex-dependent neurobiological features of prenatal immune activation via TLR7

“…Immunohistochemistry for IBA-1 using 1:1000 rabbit anti-IBA-1 antibody (019-19471, Wako Chemicals, Osaka, Japan) was performed [22]. For quantification of microglia density, whole-section montages were created using a confocal laser scanning microscope (TCS SP8, Leica, Wetzler, Germany) with Leica Application Suite software and a ×10 objective.…”