Search

22q11.2 deletion syndrome is characterised by a well defined microdeletion that is associated with a high risk of neuropsychiatric disorders, including intellectual disability, schizophrenia, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety disorders, seizures and epilepsy, and early-onset Parkinson’s disease. Preclinical and clinical data reveal substantial variability of the neuropsychiatric phenotype despite the shared underlying deletion in this genetic model. Factors that might explain this variability include genetic background effects, additional rare pathogenic variants, and potential regulatory functions of some genes in the 22q11.2 deletion region. These factors might also be relevant to the pathophysiology of these neuropsychiatric disorders in the general population. We review studies that might provide insight into pathophysiological mechanisms underlying the expression of neuropsychiatric disorders in 22q11.2 deletion syndrome, and potential implications for these common disorders in the general (non-deleted) population. The recurrent hemizygous 22q11.2 deletion, associated with 22q11.2 deletion syndrome, has attracted attention as a genetic model for common neuropsychiatric disorders because of its association with substantially increased risk of such disorders.(1) Studying such a model has many advantages. First, 22q11.2 deletion has been genetically well characterised.(2) Second, most genes present in the region typically deleted at the 22q11.2 locus are expressed in the brain.(3–5) Third, genetic diagnosis might be made early in life, long before recognisable neuropsychiatric disorders have emerged. Thus, this genetic condition offers a unique opportunity for early intervention, and monitoring individuals with 22q11.2 deletion syndrome throughout life could provide important information on factors contributing to disease risk and protection. Despite the commonly deleted region being shared by about 90% of individuals with 22q11.2 deletion syndrome, neuropsychiatric outcomes are highly variable between individuals and across the lifespan. A clear link remains to be established between genotype and phenotype.(3,5) In this Review, we summarise preclinical and clinical studies investigating biological mechanisms in 22q11.2 deletion syndrome, with a focus on those that might provide insight into mechanisms underlying neuropsychiatric disorders in 22q11.2 deletion syndrome and in the general population.

BACKGROUND: Early life stress is thought to contribute to psychiatric disorders, but the precise mechanisms underlying this link are poorly understood. As neonatal stress decreases adult hippocampal neurogenesis, which, in turn, functionally contributes to many behavioral phenotypes relevant to psychiatric disorders, we examined how in vivo neonatal maternal separation (NMS) impacts the capacity of adult hippocampal neural precursor cells via epigenetic alterations in vitro. METHODS: Rat pups were separated from their dams for 3 hours daily from postnatal day (PND) 2 to PND 14 or were never separated from the dam (as control animals). We isolated adult neural precursor cells from the hippocampal dentate gyrus at PND 56 and assessed rates of proliferation, apoptosis, and differentiation in cell culture. We also evaluated the effect of DNA methylation at the retinoic acid receptor (RAR) promoter stemming from NMS on adult neural precursor cells. RESULTS: NMS attenuated neural differentiation of adult neural precursor cells but had no detectible effect on proliferation, apoptosis, or astroglial differentiation. The DNA methyltransferase (DNMT) inhibitor, 5-aza-dC, reversed a reduction by NMS of neural differentiation of adult neural precursor cells. NMS increased DNMT1 expression and decreased expression of RAR alpha. An RAR alpha agonist increased neural differentiation and an antagonist reduced retinoic acid-induced neural differentiation. NMS increased the methylated portion of RAR alpha promoter, and the DNMT inhibitor reversed a reduction by NMS of RAR alpha messenger RNA expression. CONCLUSIONS: NMS attenuates the capacity of adult hippocampal neural precursor cells to differentiate into neurons by decreasing expression of RAR alpha through DNMT1-mediated methylation of its promoter.

The brain dopaminergic system is a critical modulator of basal ganglia function and plasticity. To investigate the contribution of the dopamine D1 receptor to this modulation, we have used gene targeting technology to generate D1 receptor mutant mice. Histological analyses suggested that there are no major changes in general anatomy of the mutant mouse brains, but indicated that the expression of dynorphin is greatly reduced in the striatum and related regions of the basal ganglia. The mutant mice do not respond to the stimulant and suppressive effects of D1 receptor agonists and antagonists, respectively, and they exhibit locomotor hyperactivity. These results suggest that the D1 receptor regulates the neurochemical architecture of the striatum and is critical for the normal expression of motor activity.

This brief review draws a parallel between the drug-seeking behavior of humans addicted to amphetamine and the preference exhibited by animals for a place in which they have previously experienced the pharmacological effects of the same drug. Anatomical and pharmacological analyses suggest that nucleus accumbens dopamine receptor activation is necessary for the development of this preference. Through connections that synapse in ventral pallidum, a neural representation of accumbens dopamine receptor activation may reach the lateral nucleus of the amygdala where it could become associated with representations of existing environmental cues that also reach the lateral nucleus from cerebral cortex. When these conditioned cues are encountered on future occasions, activation of the amygdala-based association may reach either nucleus accumbens or ventral tegmental area. This neural activation either produces an excess of accumbens dopamine release or acts in synergy with a tonic level of dopamine release to cause the animal to approach and maintain contact with the conditioned cues.

Previous work has shown that conditioned stereotypy can be produced by repeated treatments with d-amphetamine or apomorphine. We replicated this phenomenon and found that, as in previous reports, the amplitude of conditioned stereotypy was about one-third that of the unconditioned stereotypy. On the basis of the hypothesis that the UCS in this conditioning situation is a specific stimulation level of dopamine receptors expressed as a peak behavioral effect (UCR), rats were exposed to the experimental boxes for a brief interval during the peak behavioral effect of the drugs. This procedure produced an amplitude of conditioned stereotypy about two-thirds that of unconditioned stereotypy. The issue of the synaptic mechanism mediating conditioned stereotypy was addressed by examining the effect of pimozide on the behavior. A dose of pimozide that completely blocked apomorphine-unconditioned stereotypy also blocked apomorphine-conditioned stereotypy with no sign of motor impairment. d-Amphetamine-conditioned stereotypy was not completely blocked by a dose of pimozide that completely blocked d-amphetamine-unconditioned stereotypy. The implications of these findings for understanding the neural basis of conditioned stereotypy are discussed.