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Bone morphogenetic proteins (BMPs), regulators of bone formation, have been implicated in embryogenesis and morphogenesis of various tissues and organs. BMP signaling plays a role in the formation of appropriate synaptic connections and development of normal neural circuits in the brain. However, physiological roles of BMP signaling in postnatal neural functions, including synaptic plasticity, remain largely unknown. Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses in the cerebellum has been suggested one neuronal mechanism underlying cerebellar functions. Here, we explored the contribution of BMP signaling to the induction of mouse cerebellar LTD. We first demonstrated that BMP2 and/or 4 were expressed in GABAergic neurons in mature networks of the cerebellar cortex. mRNA encoding BMP receptor type 1B (Bmpr1b) was expressed in the PC layer. Exogenous application of noggin, a BMP ligand inhibitor, suppressed the induction of cerebellar LTD by conjunctive stimulation, which caused normal LTD under control condition. Furthermore, mice deficient in BMPR1B exhibited attenuation of the extent of LTD induction, whereas they showed normal excitatory synaptic transmission at PF-PC synapses. These results suggest that after postnatal development, BMP signaling activated by BMPR1B, expressed in the PC layer, plays a crucial role in the facilitation of cerebellar LTD, leading to the modulation of cerebellar functions and behaviors., (© 2024 International Society for Neurochemistry.)

The loss of a cyclic change with two peaks of increased endometrial epidermal growth factor (EGF) concentration on days 2-4 and 13-14 during the estrous cycle has been linked to low fertility in repeat breeder (RB) cows. We have shown that an intravaginal infusion of osteopontin (OPN) restored the EGF profile in RB cows. The present study aimed to determine a structural element of OPN to restore the normal EGF profile and fertility. Holstein RB cows were diagnosed the EGF profile by a single examination of the endometrial EGF concentration on day 3 of the estrous cycle. Those with an altered EGF profile were intravaginally infused with OPN and its fragments on the day of insemination (day 0); the concentration of endometrial EGF was measured on day 3, and pregnancy was diagnosed on days 30-35. In Study 1, recombinant OPN (rOPN) (16 nmol), thrombin-cleaved N- and C-terminal fragments of rOPN (N-rOPN and C-rOPN, respectively), and a combination of these fragments (Th-rOPN) were infused (n = 13-20). The restoration rate of the normal EGF profile of the N-rOPN group (25.0 %) was a level in between the C-rOPN group (7.7 %) and both the rOPN (55.6 %) and Th-rOPN (64.3 %) groups. In Study 2, PBS (n = 47), rOPN (9.5 nmol, n = 83), and peptides of integrin binding motifs, GRGDSVAYGLK (peptide 1; 32, 320, and 1600 nmol), GRGDS (peptide 2; 320 and 1600 nmol), and SVAYGLK (peptide 3; 320 and 1600 nmol), were infused (n = 20-25). Restoration rates of the normal EGF profile of peptide 1 (320 and 1600 nmol) and peptide 3 (1600 nmol) groups (44.0-56.3 %) were comparable with those of the rOPN group (63.9 %) and higher than those of the PBS group (15.6 %). Restoration rates of the other groups were similar to those of the PBS group. Additional cows received infusions to determine the effect on fertility. Conception rates of the peptide 1 (320 and 1600 nmol; n = 50 each), peptide 3 (1600 nmol; n = 55), and rOPN (n = 111) groups (41.8-50.0 %) were comparable and higher than that of the PBS group (21.6 %, n = 75). In Study 3, PBS (n = 24), peptide 1 (320 nmol; n = 78), and GRGESVAYGLK peptide (peptide 4; 320 and 1600 nmol; n = 50 and 26, respectively) were infused. Restoration rates of the normal EGF profile of peptide 4 and PBS groups (16.0-19.2 %) were comparable and lower than those of the peptide 1 group (44.9 %). Thus, the SVAYGLK motif may be an OPN structural element to restore the normal EGF profile and fertility in RB cows, and the RGD motif may enhance its effect., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)