Prenatal stress alters hippocampal synaptic plasticity in young rat offspring through preventing the proteolytic conversion of pro‐brain‐derived neurotrophic factor (BDNF) to mature BDNF

• Published in: The Journal of physiology 2012-02, Vol.590 (4), p.991-1010
• Main Authors: Yeh, Che‐Ming, Huang, Chiung‐Chun, Hsu, Kuei‐Sen
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - physiology; CA1 Region, Hippocampal - pathology; CA1 Region, Hippocampal - physiology; Dams; Epilepsy; Excitatory Postsynaptic Potentials - physiology; Female; Geriatrics; Gestation; Hippocampus; In Vitro Techniques; Long-term depression; Long-term potentiation; Male; Matrix Metalloproteinase 2 - physiology; Matrix Metalloproteinase 9 - physiology; Mental disorders; Neurological diseases; Neuronal Plasticity - physiology; Neuroscience: Neurobiology of Disease; Neurotrophic factors; Plasticity (synaptic); Pregnancy; Prenatal experience; Prenatal Exposure Delayed Effects; Progeny; Protein Precursors - physiology; Proteolysis; Rats; Rats, Sprague-Dawley; Restraint, Physical - physiology; Risk factors; Sex; Stress; Stress, Psychological - physiopathology; Synaptic Transmission - physiology; t-Plasminogen activator; Tissue Plasminogen Activator - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2011.222042

Non‐technical summary  Prenatal stress (PS) has been associated with a higher risk for the development of various neurological and psychiatric disorders later in life, but the underlying mechanisms are not yet fully understood. Our results support an action mode in which PS downregulates tissue plasminogen activator levels within the hippocampus, inhibiting the proteolytic conversion of pro‐brain‐derived neurotrophic factor (pro‐BDNF) to the mature form of BDNF, thereby leading to long‐lasting alterations of the properties of synaptic plasticity. Our findings bolster the idea that stressful experience during gestation or early in life may lead to long‐lasting malfunction of the hippocampus and our PS model may be useful for the development of more effective intervention and prevention strategies.   Prenatal stress (PS) has been associated with a higher risk of development of various neurological and psychiatric disorders later in life, but the underlying mechanisms are not yet fully understood. Here, using a chronic prenatal restraint stress model where the rat dams were immobilized for 45 min three times per day during the last week of pregnancy, we explored the long‐lasting effects of PS on hippocampal synaptic plasticity in the offspring of both sexes. We found that PS switched the direction of synaptic plasticity in hippocampal CA1 region, favouring low‐frequency stimulation‐induced long‐term depression (LTD) and opposing the induction of long‐term potentiation (LTP) by high‐frequency stimulation in young (5‐week‐old) rat offspring, but these changes disappeared at adult age (8 weeks old). Fostering of PS offspring to control dams did not alter the effects of PS on LTP and LTD. In addition, PS‐induced changes in LTP and LTD induction were correlated with increasing endogenous pro‐brain‐derived neurotrophic factor (pro‐BDNF) and decreasing of the mature form of BDNF (mBDNF) levels. Furthermore, PS resulted in a significant decrease in the activity and expression of tissue plasminogen activator (tPA), a key serine protease involved in the extracellular conversion of pro‐BDNF to mBDNF. No significant differences were observed between the sexes for the effects of PS on hippocampal synaptic plasticity, the levels of pro‐BDNF and mBDNF, and tPA expression. These results suggest that PS downregulates tPA levels within the hippocampus, inhibiting the proteolytic conversion of pro‐BDNF to mBDNF, thereby leading to long‐lasting alterations of the properties of s