Abstract
Maternal immune activation (MIA) and juvenile social isolation (SI) are two most prevalent and widely accepted environmental insults that could increase the propensity of psychiatric illnesses. Using a two-hit mouse model, we examined the impact of the combination of these two factors on animal behaviors, neuronal excitability and expressions of voltage-gated sodium (Nav) and small conductance calcium-activated potassium (SK) channels in the prefrontal cortex (PFC). We found that MIA-SI induced a number of schizophrenia-related behavioral deficits. Patch clamp recordings revealed alterations in electrophysiological properties of PFC layer-5 pyramidal cells, including hyperpolarized resting membrane potential (RMP), increased input resistance and enhanced medium after-hyperpolarization (mAHP). MIA-SI also increased the ratio of the maximal slope of somatodendritic potential to the peak slope of action potential upstroke, indicating a change in perisomatic Nav availability. Consistently, MIA-SI significantly increased the expression level of Nav1.2 and SK3 channels that contribute to the somatodendritic potential and the mAHP, respectively. Together, these changes may alter neuronal signaling in the PFC and behavioral states, representing a molecular imprint of environmental insults associated with neuropsychiatric illnesses.
Highlights
Schizophrenia is a chronic and disabling psychiatric disorder affecting approximately 1% of the population worldwide (Owen et al, 2016)
Maternal immune activation (MIA)-social isolation (SI) significantly increased SK3 (p < 0.05) expression levels in prefrontal cortex (PFC) (Figure 3H). These results indicate that MIA can cause abnormal ion channel expression
We investigated behavioral and neurophysiological alterations in animals challenged with two environmental insults, MIA and SI
Summary
Schizophrenia is a chronic and disabling psychiatric disorder affecting approximately 1% of the population worldwide (Owen et al, 2016). The two-hit hypothesis suggests that a prenatal genetic or environmental first-hit can prime an individual for an adverse event later (second-hit) in life that provides substantial triggers for the full clinical syndrome to manifest (Bayer et al, 1999; Maynard et al, 2001; Feigenson et al, 2014). There is ample evidence that maternal immune activation (MIA) can act as a disease primer to increase the risk of neuropsychiatric disorders in offspring (Feigenson et al, 2014; Davis et al, 2016; Estes and McAllister, 2016), while social deprivation during adolescence has been thought to work as a second-hit leading to behavioral and biochemical changes that feature some aspects of schizophrenia Research investigating the impact of MIA-SI combination is very limited
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