Homeostatic increase in excitability in area CA1 after Schaffer collateral transection in vivo

Abstract

SUMMARY Purpose Epilepsy is a significant long-term consequence of traumatic brain injury (TBI) and is likely to result from multiple mechanisms. One feature that is common to many forms of TBI is denervation. We asked whether chronic partial denervation in vivo would lead to a homeostatic increase in the excitability of a denervated cell population. Methods To answer this question, we took advantage of the unique anatomy of the hippocampus where the input to the CA1 neurons, the Schaffer collaterals, could be transected in vivo with preservation of their outputs and only minor cell death. Key findings We observed a delayed increase in neuronal excitability, as apparent in extracellular recordings from hippocampal brain slices prepared 14 days (but not 3 days) postlesion. Although population spikes in slices from control and lesioned animals were comparable under resting conditions, application of solutions that were mildly proconvulsive (high K+, low Mg2+, low concentrations of bicuculline) produced increases in the number of population spikes in slices from lesioned rats, but not in slices from unlesioned sham controls. Denervation did not produce changes in several markers of GABAergic synaptic inhibition, including the number of GABAergic neurons, α1 GABAA receptor subunits, the vesicular GABA transporter, or miniature inhibitory postsynaptic currents. Significance We conclude that chronic partial denervation does lead to a delayed homeostatic increase in neuronal excitability, and may therefore contribute to the long-term neurological consequences of traumatic brain injury.

Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury

“…We have previously shown that this procedure results in very low amounts of cell death (Dinocourt et al 2011). We have also reported that SC transection results in a delayed and persistent increase in the excitability of the denervated CA1 cell population (Dinocourt et al 2011). We now report that this injury also triggers a delayed increase in the excitability of the CA3 cell population, as observed in ex vivo hippocampal slices from lesioned animals.…”

“…To study the consequences of a relatively selective injury to the axons of brain cells in isolation, we developed a surgical approach to transect the SC pathway and thereby damage the axons of large numbers of CA3 pyramidal cells (Dinocourt et al 2011). We have previously shown that this procedure results in very low amounts of cell death (Dinocourt et al 2011).…”

“…Schaffer collateral (SC) transections were performed as described previously (Dinocourt et al 2011). Briefly, 4-to 6-wk-old male mice were anesthetized with an intraperitoneal injection of a ketamine (40 -80 mg/kg)-xylazine (5-10 mg/kg) mixture, immobilized in a stereotactic frame (David Kopf Instruments), and placed on a heating pad to maintain normal body temperature.…”

“…Stereotactic coordinates were used to create a lesion of the SC pathway across approximately two-thirds of the length of the hippocampus that extended from the outer surface of the hippocampus to the hippocampal fissure (Dinocourt et al 2011). To assay the consequences of these lesions on neuronal excitability, we prepared ex vivo hippocampal slices from animals lesioned 1, 7, 14, and 21 days earlier and from sham-operated control animals.…”

“…1, A and C), indicating that the lesioned tissue was not strongly hyperexcitable. Increased excitability in injured hippocampus can be revealed by mildly proconvulsive manipulations that slightly perturb the balance between excitation and inhibition (Dinocourt et al 2011;McKinney et al 1997). We therefore determined the effects of application of a very low concentration of the GABA A receptor antagonist bicuculline methylchloride (0.1 M), a concentration 100-fold lower than normally used to elicit epileptiform discharge (Haas and Ryall 1980;Schwartzkroin and Prince 1980), on population spikes in slices from lesioned and sham-operated control mice.…”