OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency.

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.

A comparison of structure and thermal behavior in human plasma lipoprotein(a) and low-density lipoprotein. Calorimetry and small-angle X-ray scattering.

Differential scanning calorimetry (DSC) and small-angle X-ray scattering (SAXS) studies have been performed to investigate the structural properties of lipoprotein(a) [Lp(a)] and low-density lipoprotein (LDL) obtained from the same donor. In addition, a comparison was made between autologous LDL and the remnant particle Lp(a-) obtained by removal of apo(a) through chemical reduction. With Lp(a), three distinct thermal transitions have been observed: the first one around 20 degrees C, arising from the core-located apolar lipids, similar to LDL but with a significantly lower melting temperature as compared to LDL of the same donor. The second one, at 55.7 +/- 0.25 degrees C, can be attributed to apo(a), since it was found to be absent in Lp(a-) and LDL, whereas isolated apo(a) in aqueous solution exhibited a similar transition. The third transition, at 80.4 +/- 0.9 degrees C, corresponds to apo-B100 protein unfolding. The low melting temperature of the core lipids in Lp(a) is preserved in Lp(a-); this suggests that the apolar lipid interactions are unaffected by apo(a) binding, and that the difference in the core melting behavior between Lp(a) and LDL is due to a different stabilization through interaction between the apolar core and the surface monolayer lipids. SAXS curves exhibited qualitatively the same characteristic features for LDL, Lp(a), and Lp(a-). Thus, the SAXS results showed that no major deviations from spherical particle shape occur with Lp(a), indicating that apo(a) wraps around the particle surface without major globular protrusions into the aqueous surrounding.(ABSTRACT TRUNCATED AT 250 WORDS)