Journal Article

D-Cycloserine Restores Experience-Dependent Neuroplasticity after Traumatic Brain Injury in the Developing Rat Brain

Cai, Yan, Hovda, David A., Buen, Floyd, Harris, Neil G., Baquing, Mary Anne T., Ponnaluri, Aditya, Sta Maria, Naomi S., Reger, Maxine L., Giza, Christopher C.

2017

Overview

Traumatic brain injury (TBI) in children can cause persisting cognitive and behavioral dysfunction, and inevitably raises concerns about lost potential in these injured youth. Lateral fluid percussion injury (FPI) in weanling rats pathologically affects hippocampal N-methyl-d-aspartate receptor (NMDAR)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated glutamatergic neurotransmission subacutely within the first post-injury week. FPI to weanling rats has also been shown to impair enriched-environment (EE) induced enhancement of Morris water maze (MWM) learning and memory in adulthood. Recently, improved outcomes can be achieved using agents that enhance NMDAR function. We hypothesized that administering D-cycloserine (DCS), an NMDAR co-agonist, every 12 h (i.p.) would restore subacute glutamatergic neurotransmission and reinstate experience-dependent plasticity. Postnatal day 19 (P19) rats received either a sham or FPI. On post-injury day (PID) 1–3, animals were randomized to saline (Sal) or DCS. Firstly, immunoblotting of hippocampal NMDAR and AMPAR proteins were measured on PID4. Second, PID4 novel object recognition, an NMDAR- and hippocampal- mediated working memory task, was assessed. Third, P19 rats were placed in an EE (17 days), and MWM performance was measured, starting on PID30. On PID4, DCS restored reduced NR2A and increased GluR2 by 54%, and also restored diminished recognition memory in FPI pups. EE significantly improved MWM performance in shams, regardless of treatment. In contrast, FPI-EE-Sal animals only performed to the level of standard housed animals, whereas FPI-EE-DCS animals were comparable with sham-EE counterparts. This study shows that NMDAR agonist use during reduced glutamatergic transmission after developmental TBI can reinstate early molecular and behavioral responses that subsequently manifest in experience-dependent plasticity and rescued potential.

• Publisher: SAGE Publications,Mary Ann Liebert, Inc
• Subject: Animal cognition / Animals / Brain damage / Brain Injuries, Traumatic - drug therapy / Brain Injuries, Traumatic - rehabilitation / Combined Modality Therapy / Cycloserine - administration & dosage / Cycloserine - pharmacology / Disease Models, Animal / Environment / Excitatory Amino Acid Agonists - administration & dosage / Excitatory Amino Acid Agonists - pharmacology / Male / Neurobiology / Neurological Rehabilitation / Neuronal Plasticity - drug effects / Original / Pharmacology / Rats / Rats, Sprague-Dawley / Receptors, AMPA / Receptors, N-Methyl-D-Aspartate - agonists / Receptors, N-Methyl-D-Aspartate - metabolism / Rodents