The prefrontal cortex is highly vulnerable to traumatic brain injury resulting in the dysfunction of many high-level cognitive and executive functions such as planning, information processing speed, language, memory, attention, and perception. All of these processes require some degree of working memory. Interestingly, in many cases, post-injury working memory deficits can arise in the absence of overt damage to the prefrontal cortex. Recently, excess GABA-mediated inhibition of prefrontal neuronal activity has been identified as a contributor to working memory dysfunction within the first month following cortical impact injury of rats. However, it has not been examined if these working memory deficits persist, and if so, whether they remain amenable to treatment by GABA antagonism. Our findings show that working memory dysfunction, assessed using both the delay match-to-place and delayed alternation t-maze tasks, following lateral cortical impact injury persists for at least 16 weeks post-injury. These deficits were found to be no longer the direct result of excess GABA-mediated inhibition of medial prefrontal cortex neuronal activity. Golgi staining of prelimbic pyramidal neurons revealed that TBI causes a significant shortening of layer V/VI basal dendrite arbors by 4 months post-injury, as well as an increase in the density of both basal and apical spines in these neurons. These changes were not observed in animals 14 days-post-injury, a time point at which administration of GABA receptor antagonists improves working memory function. Taken together, the present findings, along with previously published reports, suggest that temporal considerations must be taken into account when designing mechanism-based therapies to improve working memory function in TBI patients.
Excessive glutamate receptor stimulation can produce rapid disruption of dendritic morphology, including dendritic beading. We recently showed that transient N-methyl-d-aspartic acid (NMDA) exposure resulted in irreversible loss of synaptic function and loss of microtubule associated protein 2 (MAP2) from apical dendrites. The present study examined the initiation and progression of dendritic injury in mouse hippocampal slices following this excitotoxic stimulus. NMDA exposure (30 microM, 10 min) produced irregularly shaped dendritic swellings, evident first in distal apical dendrite branches, and later (20-90 min) involving most proximal dendrites. Over the same time course, immunoreactivity for the microtubule-associated protein MAP2 was progressively lost from apical dendrites, and increased in CA1 somata. This damage and MAP2 loss was Ca2+-dependent, and was not reversible within the time course of these experiments (90 min post-NMDA washout). Formation of regularly-spaced, spherical dendritic varicosities (dendritic beading) was rarely observed, except when NMDA was applied in Ca2+-free ACSF. Under these conditions, beading appeared predominant in interneurons, as assessed from experiments with GAD67-GFP (Deltaneo) mice. Ca2+-removal was associated with significantly better preservation of dendritic structure (MAP2) following NMDA exposure, and other ionic fluxes (sensitive to Gd3+ and spermine) may contribute to residual damage occurring in Ca2+-free conditions. These results suggest that irregularly shaped dendritic swelling is a Ca2+-dependent degenerative event that may be quite different from Ca2+-independent dendritic beading, and can be a predominant type of injury in CA1 pyramidal neurons in slices.
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