D-Cycloserine Restores Experience-Dependent Neuroplasticity after Traumatic Brain Injury in the Developing Rat Brain
Naomi S Sta Maria1,2, Maxine L Reger1,3, Yan Cai1
11 Department of Neurosurgery, UCLA Brain Injury Research Center , Los Angeles, California.
Insights
D-cycloserine (DCS) administration after developmental traumatic brain injury (TBI) in rats restored N-methyl-D-aspartate receptor (NMDAR) function and cognitive deficits. This NMDAR agonist treatment reinstated experience-dependent plasticity, rescuing lost potential in injured youth.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Neuropharmacology
Background:
- Pediatric traumatic brain injury (TBI) can lead to lasting cognitive and behavioral impairments.
- Lateral fluid percussion injury (FPI) in young rats disrupts hippocampal glutamatergic neurotransmission.
- FPI impairs the benefits of enriched environments on learning and memory in adulthood.
Purpose of the Study:
- To investigate if D-cycloserine (DCS), an N-methyl-D-aspartate receptor (NMDAR) co-agonist, can restore glutamatergic function and plasticity after developmental TBI.
- To assess DCS's effect on molecular, behavioral, and experience-dependent plasticity outcomes following FPI in weanling rats.
Main Methods:
- Weanling rats (postnatal day 19) underwent either sham or lateral fluid percussion injury (FPI).
- Animals received saline or D-cycloserine (DCS) treatment on post-injury days 1-3.
- Evaluated hippocampal NMDAR/AMPAR protein levels, novel object recognition memory, and Morris water maze performance after enriched environment exposure.
Main Results:
- DCS treatment on post-injury day 4 restored reduced NR2A and increased GluR2 levels in FPI rats.
- DCS administration improved novel object recognition memory in FPI pups.
- In enriched environments, DCS-treated FPI rats showed cognitive performance comparable to sham-treated controls.
Conclusions:
- NMDAR agonist administration during the subacute phase after developmental TBI can restore glutamatergic transmission.
- DCS treatment facilitates the reinstatement of early molecular and behavioral responses.
- This approach rescues experience-dependent plasticity and mitigates cognitive deficits, potentially restoring lost potential.
Abstract:
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.
