Neuroinflammation as a risk factor for attention deficit hyperactivity disorder

Abstract

Attention Deficit Hyperactivity Disorder (ADHD) is a persistent, and impairing pediatric-onset neurodevelopmental condition. Its high prevalence, and recurrent controversy over its widespread identification and treatment, drive strong interest in its etiology and mechanisms. Emerging evidence for a role for neuroinflammation in ADHD pathophysiology is of great interest. This evidence includes 1) the above-chance comorbidity of ADHD with inflammatory and autoimmune disorders, 2) initial studies indicating an association with ADHD and increased serum cytokines, 3) preliminary evidence from genetic studies demonstrating associations between polymorphisms in genes associated with inflammatory pathways and ADHD, 4) emerging evidence that early life exposure to environmental factors may increase risk for ADHD via an inflammatory mechanism, and 5) mechanistic evidence from animal models of maternal immune activation documenting behavioral and neural outcomes consistent with ADHD. Prenatal exposure to inflammation is associated with changes in offspring brain development including reductions in cortical gray matter volume and the volume of certain cortical areas -parallel to observations associated with ADHD. Alterations in neurotransmitter systems, including the dopaminergic, serotonergic and glutamatergic systems, are observed in ADHD populations. Animal models provide strong evidence that development and function of these neurotransmitters systems are sensitive to exposure to in utero inflammation. In summary, accumulating evidence from human studies and animal models, while still incomplete, support a potential role for neuroinflammation in the pathophysiology of ADHD. Confirmation of this association and the underlying mechanisms have become valuable targets for research. If confirmed, such a picture may be important in opening new intervention routes.

Keywords: Maternal immune activation; Neurodevelopmental.

Figure 1.

Neural and behavioral changes of offspring born from mothers injected with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly(I:C)) associated with changes observed in ADHD. Maternal immune activation (MIA) by LPS or poly(I:C) results in an increase of in utero cytokines altering the inflammatory environment of the developing offspring. MIA results in structural changes in volume and grey matter volume are observed in the anterior cingulate cortex, basal ganglia, dorsolateral prefrontal cortex, inferior prefrontal cortex, and orbitofrontal cortex. Functional changes observed in MIA offspring are alterations in the homeostatic levels of the neurotransmitters serotonin (5-HT), dopamine (DA), and glutamate (Glu) as well as a reduction in tryptophan hydroxylase (TPH2), the rate limiting step of 5-HT synthesis. In addition, alterations are observed in functionality of serotonin reuptake transporters (SERT) and dopamine transporters (DAT), dopamine receptors (D1/D2), metabotropic glutamate receptors (mGlu2), ionotropic glutamate receptors (NR1/NR2A), and NMDA receptors (NMDAR). Changes in these neural outcomes are associated with behavioral outcomes of increased hyperactivity and impulsivity along side decreases in attention and learning and memory.