Dietary branched chain amino acids ameliorate injury-induced cognitive impairment

Abstract

Neurological dysfunction caused by traumatic brain injury results in profound changes in net synaptic efficacy, leading to impaired cognition. Because excitability is directly controlled by the balance of excitatory and inhibitory activity, underlying mechanisms causing these changes were investigated using lateral fluid percussion brain injury in mice. Although injury-induced shifts in net synaptic efficacy were not accompanied by changes in hippocampal glutamate and GABA levels, significant reductions were seen in the concentration of branched chain amino acids (BCAAs), which are key precursors to de novo glutamate synthesis. Dietary consumption of BCAAs restored hippocampal BCAA concentrations to normal, reversed injury-induced shifts in net synaptic efficacy, and led to reinstatement of cognitive performance after concussive brain injury. All brain-injured mice that consumed BCAAs demonstrated cognitive improvement with a simultaneous restoration in net synaptic efficacy. Posttraumatic changes in the expression of cytosolic branched chain aminotransferase, branched chain ketoacid dehydrogenase, glutamate dehydrogenase, and glutamic acid decarboxylase support a perturbation of BCAA and neurotransmitter metabolism. Ex vivo application of BCAAs to hippocampal slices from injured animals restored posttraumatic regional shifts in net synaptic efficacy as measured by field excitatory postsynaptic potentials. These results suggest that dietary BCAA intervention could promote cognitive improvement by restoring hippocampal function after a traumatic brain injury.

Investigations on Alterations of Hippocampal Circuit Function Following Mild Traumatic Brain Injury

“…Further studies employed a mix of molecular biology techniques and electrophysiology to investigate the mechanism behind the observed imbalance of excitatory/inhibitory synaptic transmission (11). Importantly, these studies employed behavior not only to demonstrate a cognitive impairment post-TBI, but also to validate the effectiveness of a dietary treatment strategy derived from the results gained from using our combinatorial approach.…”

Pathophysiology and Treatment of Memory Dysfunction After Traumatic Brain Injury

“…Branched chain amino acids (BCAAs) are key amino acids involved in de novo glutamate synthesis [142]. We have found that dietary BCAA therapy restores limbic E/I balance and ameliorates hippocampal-dependent contextual fear memory impairment in a mild/moderate FPI mouse model [143]. Furthermore, we have demonstrated that BCAA therapy mitigates injury-induced inability to maintain wakefulness [144••].…”

Craniotomy: True Sham for Traumatic Brain Injury, or a Sham of a Sham?

“…Local to global neurological dysfunction associated with TBI is not only caused by the primary immediate insult, but is also caused by the delayed secondary cascade of biochemical and metabolic pathological events. These include impaired aerobic metabolism, altered calcium homeostasis, disrupted amino acid metabolism, and activated inflammatory responses (Alves et al, 2005;Bartnik et al, 2007;Cole et al, 2010;Deshpande et al, 2008;Faria et al, 2007;He et al, Traumatic brain injury is not a single entity. Rather it is a disorder caused by multiple mechanisms, including low-and high-velocity penetrating injury, blunt trauma, diffuse axonal injury, and blast.…”