Abstract
Mental health disorders are manifested in families, yet cannot be fully explained by classical Mendelian genetics. Changes in gene expression via epigenetics present a plausible mechanism. Anxiety often leads to avoidant behaviors which upon repetition may become habitual, maladaptive and resistant to extinction as observed in obsessive compulsive disorders (OCD). Psychophysical models of OCD propose that anxiety (amygdala) and habits (dorsolateral striatum, DLS) may be causally linked. The amygdala activates spiny projection neurons in the DLS. Repetitive amygdala terminal stimulation in the DLS elicits long term OCD-like behavior in mice associated with circuitry changes and gene methylation-mediated decrease in the activity of protein phosphatase 1 (PP1). Treatment of OCD-like grooming behavior in Slitrk5, SAPAP3, and laser-stimulated mice with one dose of RG108 (DNA methyltransferase inhibitor), lead to marked symptom improvement lasting for at least one week as well as complete reversal of anomalous changes in circuitry and PP1 gene methylation.
Highlights
D mediated decrease in the activity of protein phosphatase 1 (PP1)
T Mental health disorders repeatedly arise in families and often co-occur in twins, but most cases cannot be explained by classical Mendelian genetics
We have recently shown that the basal and lateral nuclei of the amygdala (BLA) send functional projections directly to spiny projection neurons (SPNs) in the dorsolateral striatum (DLS), and that these projections target D1s and D2s in wild type (WT) mice[40]
Summary
TEpigenetic modulator drugs reduce OCD-like behavior in two different genetic mouse models of OCD. DNMT inhibition reversed laser stimulation-induced circuitry changes, such that BLA-DLS inputs resembled (functionally and morphologically) those in unstimulated WT mice. The high degree of alignment between observed behavioral and regulatory effects of epigenetic modulation in both gene knockout and laser stimulation based mouse models point to the key physiological role of epigenetic mechanisms in OCD-like behaviors as well as likely clinical relevance of SAPAP3 and Stilrk[5] KO mice as animal models. I (PP1 gene methylation) changes associated with laser stimulation-induced OCD-like behavior in mice indicate long-term potentiation (LTP) in the BLA-DLS circuitry, affecting D1s. The BLA modulates the DLS activity via the two opposing pathways of movement stimulation (D1) and movement inhibition (D2), whose anomalies we showed to be associated with OCD-like behaviors. A anisms may lead to new treatments for obsessive-compulsive disorder and many other pathologies characterized by aberrant synaptic plasticity and circuitry dysregulation persisting due to epigenetic changes
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