Maternal factors - pregnancy, calcium homeostasis and implications for development


Maternal viral infection during pregnancy has been hypothesised to alter fetal brain development indirectly - maternal inflammatory response was shown in vitro to interfere in neuronal development and CNS organisation [2273013, 12666123, 17029701] (also see Immunity/Inflammation for elevation in cytokine levels during pregnancy). In additon to cytokines and other inflammatory mediators, maternal antibodies have been suggested to play a possible role in some forms of neurodevelopmental disorders, as the mice injected with serum containing maternal brain antibodies exibited changes in fields of exploration and motor coordination [12666123].

Another study found that prenatal exposure to antibodies from mothers of children with autism (MCAD) also produced neurobehavioral alterations in mice - displayed anxiety-like behavior on and had a greater magnitude of startle following acoustic stimulation. On a social interaction paradigm, adult mice had alterations of sociability. Pilot studies of immune markers in MCAD IgG-exposed embryonic brains suggest evidence of cytokine and glial activation. These studies demonstrate that the transplacental passage of IgG from MCAD is capable of inducing long-term behavioral consequences [19362378].

The role of antibodies to several neuronal and muscle ion channels in the etiology of neuromuscular transmission disorders is well known. For example the ability of anti-tissue antibodies to cause contraction of smooth muscle cells is thought to be due to their interaction and modulation of with plasma membrane calcium channels, with the most likely involvement of LTCC [8288445].

Congenital Heart Block (CHB) is a congenital heart condition caused by maternal autoantibody-mediated disturbance of LTCC in the heart of the newborn - maternal antibodies recognize human LTCC alpha(1C)-protein and functionally inhibit the expressed current. It should be noted that mothers of affected children frequently suffer autoimmune diseases, and that the fetal heart appears to be uniquely vulnerable and that the mother's heart is almost never affected with complete heart block despite exposure to identical circulating levels of autoantibodies [11427485].

As voltage-gated ion channels are expressed in the brain as well as at the neuromuscular junction and in the heart, and it is often suggested that antibodies to some CNS channels could be associated with CNS disease. It can also be argued that a mechanism of similar nature to CHB could be at play in autism, where maternal autoantibodies could be affecting calcium channels and thus dysregulating ionic currents in neurons, glial or endothelial cells that line brain vessels.

Recent evidence has shown that antibodies directed against angiotensin II type I receptors are also highly associated with preeclampsia. It has been suggested that maternal antibodies could activate these receptors and subsequently plasma calcium channels, leading to an increase in intracellular calcium levels and to downstream activation of calcium signaling pathways [15381659, 12593997].

Plasma serotonin levels in mothers of ASD subjects was observed in one study to be significantly lower than in control mothers. Low maternal serotonin levels were proposed to be a risk factor for autism through effects on fetal brain development, especially in the light of a recent murine study showing that maternally-derived serotonin, as opposed to fetus-derived, is crucial for murine embryonic development [6939857, 17182745]. Worth noting is that lowered serotonin levels are a frequent feature of viral infections, since maternal viral infection and/or reactivation is a proposed risk factor in etiology of autism [16842443, 2771632, 9026369].

The mechanism behind the effects of serotonin on brain development and function is hypothesised to be at least in part linked to the inhibitory effects of serotonin on voltage-gated calcium currents, most likely through activation of its 5-HT1A and possibly 5-HT2A receptors [11494406, 8118677, 11976386]. The importance of serotonin in promoting directed neuronal migration is hypothesised to be due to its G-protein-dependent modulation of voltage-gated calcium channels in the migrating cell [12401168]. Of interest here is that 5-HT1A agonists, in additon to reducing ischemic brain injury in vitro, have been proposed as possible agents for prevention of (virally-induced) neuro-psychiatric disorders (see AIDS ref above, also Infectious_Agents).

In the context of prenatal/maternal infection as a possible risk factor, worth noting is the greater occurrence of placental trophoblast inclusions observed recently in ASD individuals compared to controls [16806106], since infectious agents have been observed to persist and replicate in placental trophoblast cells, often causing their inclusions [2446593, 11743054, 6283965, 3918685]. In additon, human placental trophoblasts express voltage gated calcium channels, and their activation induces secretion of corticotropim releasing hormone (CRH), thought to be closely linked to acute or chronic metabolic, psychological, physical or infectious stress during pregnancy. CRH hypersecretion has been associated to depression and anxiety-related disorders, anorexia nervosa and neurodegenerative diseases [10999834, 17127316]. For example it has been shown that exposure of animals to stressful experience (restrain stress) during pregnancy can exert effects on calcium ion channels of offspring hippocampal neurons and that such calcium channel disturbances may play a role in prenatal stress-induced neuronal loss and oxidative damage in offspring brain [17123551].



Thyroid function as a risk factor and involvement of calcium signalling

Familial autoimmune thyroid disease has recently been identified as a risk factor for regression in children with ASD and hypothyroid hormone deficiency in early development has been proposed to cause central nervous system damage that could lead to emergence of autistic symptoms [16598435, 1577897].

Thyroid hormone is essential for the development and maturation of the CNS in mammals. Deficency of the hormone during development negatively affects performance in tasks of learning and memory in rodents, and was shown to cause abnormalities of the CNS such as incomplete maturation of neurons and glial cells, reduction in synaptic densities and myeling deficits. Rodent with mild and transient neonatal hypothyroidism has been proposed as a novel model for autism.

It has been speculated that behavioral deficits associated with developmental hypothyroidism are due to enhanced calcium influx through LTCC [15673845] and/or impairments of the calcium ATPase activity during critical stages of brain development [16293371]. Amongst other things thyroid hormone regulates neurotransmitter release in neonatal rat hippocampus and hypothyroid rats exhibit an increase in the calcium-dependent neurotransmitter secretion (see Neurotransmitters), an effect that could be reversed by administering thyroid hormone [11882369]. In additon, a recent study demonstrated that thyroid hormone insufficiency during early postnatal period permanently alters expression of calcium binding protein parvalbumin (PV) in GABAerigic interneurons and compromises their inhibitory function [17008398].

In cardiac tissue, hypothyroidism impairs the early postnatal maturation of voltage gated calcium channels as regards both their distribution and mRNA expression. L-type and T-type calcium channels, as well as the ryanodine channel are amongst those affected by actions of thyroid hormone. Hyperthyroidism is associated with increases in cardiac LTCC currents, and changes in thyroid status markedly influence cardiac contractile and electrical activity. These mechanism are thought to be the likely causes of development of heart failure in hyperthyroidism [9539869, 16238192, 12914768, 10710339]