Acute Injury to Superficial Cortex Leads to a Decrease in Synaptic Inhibition and Increase in Excitation in Neocortical Layer V Pyramidal Cells

Abstract

Ling. Acute injury to superficial cortex leads to a decrease in synaptic inhibition and increase in excitation in neocortical layer V pyramidal cells. J Neurophysiol 97: 178 -187, 2007. First published September 20, 2006 doi:10.1152/jn.01374.2005. Injury to the superficial layers of cerebral cortex produces alterations in the synaptic responses of local circuits that promote the development of seizures. To further delineate the specific changes in synaptic strength that are induced by this type of cortical injury, whole cell voltage-clamp recordings were used to examine evoked and spontaneous synaptic events from layer V pyramidal cells in coronal slices prepared from surgically traumatized rat neocortices in which the superficial third of the cortex (layers I, II, and part of III) was removed. Slices from intact neocortices were used as controls. Examinations of fast inhibitory postsynaptic currents (IPSCs) indicated that traumatized slices were disinhibited, exhibiting evoked IPSCs (eIPSCs) with lower peak amplitudes. Measurements of spontaneous IPSCs (sIPSCs) revealed no difference in the mean amplitudes of sIPSCs recorded in traumatized versus control slices. However, the mean sIPSC frequency was lower in traumatized slices, indicative of a decrease in GABA release at these inhibitory synapses. Traumatized slices also displayed an increase in synaptic excitation, exhibiting spontaneous EPSCs (sESPCs) with larger peak amplitudes and higher frequencies. Peak-scaled nonstationary fluctuation analysis of sEPSCs and sIPSCs was used to obtain estimates of the unit conductance and number of functional receptor channels. EPSC and IPSC channel numbers and IPSC unit conductance did not differ between traumatized and intact slices. However, the mean unit conductance of EPSCs was higher (ϩ25%) in traumatized slices. These findings suggest that acute injury to the superficial neocortical layers results in a disinhibition of cortical circuits that stems from a decline in GABA release likely due to the loss of superficial inhibitory interneurons and an enhancement of synaptic excitation consequent to an increase in the AMPA receptor unit conductance.

Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

“…Intrinsic excitability refers to the propensity of a neuron to fire an action potential and is governed by the membrane properties, currents, and channels expressed by a neuron. Alterations to intrinsic excitability have been shown in numerous models of CNS disorders (Willmore 1990;Yang et al 2007) and may contribute to the pathophysiology of rmTBI. To examine for changes in intrinsic excitability induced by rmTBI, we recorded under current clamp the response of sham-injured (n ϭ 10) or rmTBI (n ϭ 14) neurons to a series of hyperpolarizing and depolarizing steps (Ϫ100 pA to 350 pA, 50-pA steps).…”

“…As a result, mTBI is often referred to as an "invisible wound" and is difficult to diagnose. Whether a single mTBI induces long-term deficits is currently a source of significant debate Klein et al 1996;Konrad et al 2011;Vanderploeg et al 2005;Vasterling et al 2012;Yuh et al 2014). It is clear, however, that when a patient receives multiple mTBIs within a short period of time it results in more severe symptoms, a longer recovery period, and increased risk for serious long-term consequences (Guskiewicz et al 2000(Guskiewicz et al , 2003.…”

Excitatory synaptic transmission and network activity are depressed following mechanical injury in cortical neurons

“…Li and Prince (2002) report increased sEPSC and mEPSC frequency and amplitude in layer V pyramidal neurons in slices from chronically injured neocortex (Li and Prince 2002). Similarly, deafferentation due to the removal of superficial cortical layers in an in vitro neocortical slice preparation results in increased sEPSC amplitude and frequency in layer V pyramidal neurons 2-8 h after injury (Yang et al 2007). Changes in excitatory synaptic function occur in the context of complex pathophysiology that includes changes in intrinsic membrane properties (Avramescu and Timofeev 2008;Prince and Tseng 1993), axonal sprouting (Salin et al 1995), increased excitatory synaptic connectivity (Avramescu and Timofeev 2008;Jin et al 2006), and decreased inhibitory synaptic transmission (Li and Prince 2002;Yang et al 2007).…”

“…Similarly, deafferentation due to the removal of superficial cortical layers in an in vitro neocortical slice preparation results in increased sEPSC amplitude and frequency in layer V pyramidal neurons 2-8 h after injury (Yang et al 2007). Changes in excitatory synaptic function occur in the context of complex pathophysiology that includes changes in intrinsic membrane properties (Avramescu and Timofeev 2008;Prince and Tseng 1993), axonal sprouting (Salin et al 1995), increased excitatory synaptic connectivity (Avramescu and Timofeev 2008;Jin et al 2006), and decreased inhibitory synaptic transmission (Li and Prince 2002;Yang et al 2007). Thus, although the findings of these studies would appear at face value to contradict our study, these other cortical models correspond to more focal and severe penetrating brain injuries, whereas our model directly assessed the effect of mild, non-lethal injury, such as that encountered in closed head concussion.…”

Connexin36 knockout mice display increased sensitivity to pentylenetetrazol-induced seizure-like behaviors

“…pyramidal cells (Yang, et al 2007). Furthermore, our group has recently reported in the isolated cortical slice model that gap junction blockade with low-dose mefloquine and carbenoxolone increases seizure-like event frequency and amplitude (Voss, et al 2009).…”