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Restoration of Experience-Dependent Plasticity through Enhancement of Glutamatergic Neurotransmission after Developmental Traumatic Brain Injury


Traumatic brain injury (TBI) in children can cause persistent cognitive and behavioral dysfunction and inevitably raises concerns about lost potential or the inability to return to "normalcy" in these injured youths. After a diffuse model of traumatic brain injury, lateral fluid percussion injury (FPI), there is evidence of pathological activation of major ionotropic glutamate receptors, N-methyl-D-aspartate receptors (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazole-proprionate receptors (AMPAR), and an NMDAR-mediated downstream effector (calcium-calmodulin dependent protein kinase II - CAMKII) in the hippocampus. These injury-induced molecular alterations have been shown to last longer in the developing brain compared to the mature brain. Moreover, these molecules are crucial mediators of experience-dependent plasticity and normal cerebral development, which prime the synaptic milieu for pro-plasticity circuitry formation. FPI administered to weanling rats has further been shown to impair enriched environment (EE)-induced experience-dependent plasticity that persists into adulthood.

Glutamate neurotransmission is essential in normal physiology, maturation and plasticity, and is greatly perturbed by TBI. While spontaneous recovery still occurs, the young injured brain is less receptive to the benefits of behavioral experience. Injured subjects may still recover to pre-injury baseline, depending on the severity of injury; however, they could demonstrate altered development and never perform at the same level as their non-injured peers. This is translated into lost potential. Clinically, however, glutamate blockade as a therapeutic intervention has failed to show neuroprotection or promote functional recovery clinically. Recently there is a shift in focus to agents that target the glutamatergic system positively. NMDAR agonists have facilitated recovery of learning and memory after experimental TBI in the mature brain. Particularly, when treated with NMDA or D-cycloserine (DCS), a partial agonist at the NMDAR glycine-binding site, brain injured animals have shown rapid functional recovery.

The central hypothesis of this dissertation is that the administration of an NMDAR agonist (DCS) during the post-injury period of diminished glutamatergic neurotransmission would do the following two things: 1) restore hippocampal glutamate-mediated markers of plasticity in the post-subacute time point (one week post-injury); and 2) reinstate hippocampal-dependent, EE-induced experience-dependent plasticity. This translates into the restoration of lost plasticity after developmental FPI.

Twenty-four to seventy-two hours post-injury, DCS was administered intra-peritoneally, once every 12 hours, to postnatal day 19 rats that received either sham or FPI. In Chapter 1, the effects of DCS treatment on glutamate-mediated pro-plasticity molecules (NMDAR, AMPAR, and CAMKII) were investigated on post-injury day four (PID4) using western blotting. At the same time point, the effects of DCS were assessed using novel object recognition (NOR), a hippocampally-mediated, NMDAR-dependent working memory task. Not only was NOR used as a functional assay of NMDAR-mediated neurotransmission in the subacute PID4 time point, but also as measure of capacity for EE-induced plasticity. The ability to distinguish novelty would be essential in benefiting from the EE experience.

In Chapter 2, following either an FPI or a sham procedure, postnatal day 19 rat pups were differentially housed in standard cages or an EE for 17 days. The extent of EE-induced experience-dependent plasticity was measured by testing the animals' performance in a spatial learning paradigm (Morris water maze) thirty days after injury when they have matured. How early DCS treatment after developmental FPI influences experience-dependent plasticity was investigated. From the results of Chapter 1 and 2, enhancing NMDAR function during the period of reduced glutamatergic transmission following traumatic brain injury in young rats can reinstate molecular and behavioral responses. This subsequently manifests as rescued potential and experience-dependent plasticity later with long-lasting beneficial consequences.

Furthermore, glutamatergic neural activity can now be indirectly quantified by mapping the coupled change in relative cerebral blood volume (rCBV) using pharmacological magnetic resonance imaging (phMRI). The noninvasive and translatable potential of this measure allows for a powerful within subject experimental design. In Chapter 3, a stimulation dose of an NMDAR agonist (DCS) was used to induce increases of rCBV specific to the hippocampus in intact developing rats. This evoked change in the NMDAR-mediated rCBV was explored as a physiological biomarker for FPI. Clinical translational potential for this type of noninvasive diagnostic measure include the ability to assess the extent of diminished NMDAR-mediated glutamatergic activity and the efficacy of a glutamate-mediated treatment after TBI.

Using converging operations, this dissertation demonstrates that NMDAR-mediated glutamatergic dysfunction is an underlying mechanism of long-lasting impaired plasticity after developmental FPI. NMDAR agonist treatment after FPI during a critical period of development can reinstate the pro-plasticity milieu, which is crucial for acquiring beneficial experience-dependent plasticity.

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