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Larry S Benardo

Publications and source records attributed to Larry S Benardo.

8 recordsLinked to original sources
PubMed2006

Acute injury to superficial cortex leads to a decrease in synaptic inhibition and increase in excitation in neocortical layer V pyramidal cells.

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 (+25%) 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.

Acute Disease↗
PubMed2006

Protein kinase Mzeta enhances excitatory synaptic transmission by increasing the number of active postsynaptic AMPA receptors.

Protein kinase Mzeta (PKMzeta), a constitutively active, atypical PKC isoform, enhances synaptic strength during the maintenance of long-term potentiation (LTP). Here we examine the mechanism by which PKMzeta increases synaptic transmission. Postsynaptic perfusion of PKMzeta during whole-cell recordings of CA1 pyramidal cells strongly potentiated the amplitude of AMPA receptor (AMPAR)-mediated miniature EPSCs (mEPSCs). Nonstationary fluctuation analysis of events recorded before and after PKMzeta enhancement showed that the kinase doubled the number of functional postsynaptic AMPAR channels. After sustained potentiation, application of a PKMzeta inhibitor reversed the increase in functional channel number to basal levels, suggesting that persistent increase of PKMzeta is required to maintain the postsynaptic localization of a mobile subpopulation of receptors. The kinase did not affect other sites of LTP expression, including presynaptic transmitter release, silent synapse conversion, or AMPAR unit conductance. Thus PKMzeta functions specifically to establish and maintain long-term increases in active postsynaptic AMPAR number.

Animals↗
PubMed2004

Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex.

It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation-inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABA(A) receptor responses in pyramidal cells. This suggests that the therapeutic actions of nootropic agents may be partly mediated through enhanced cortical GABAergic inhibition, and not solely through the direct modification of excitation, as previously thought.

Animals↗
PubMed2003

Prevention of epilepsy after head trauma: do we need new drugs or a new approach?

Annually in the U.S. about 500,000 head injuries are severe enough to require hospitalization. Past studies of severe head trauma estimate the risk of late seizures, which are synonymous with epilepsy, to be from 26 to 53%. Furthermore, head trauma accounts for 5% of all epilepsy cases and 20% of symptomatic epilepsy. Although potentially preventable, no effective prophylaxis for posttraumatic epilepsy currently exists. Prior attempts to prevent posttraumatic epileptogenesis used various anticonvulsants, usually given many hours after injury. Generally these studies showed these agents suppressed seizures in the first week after trauma, but had no effect on the incidence of late posttraumatic seizures. Brain trauma engages a rapid excitotoxic process triggered by glutamate release, similar to that seen with ischemia. For ischemic cell damage early and rapid delivery of agents has been a key to rescuing or protecting neurons. Yet, no study has addressed whether the rapidity of drug delivery is critical in the prophylaxis of late seizures. Perhaps excitotoxicity proximate to the brain injury also leads to the neurological deficits seen after severe trauma, initiating and promoting epileptogenesis, and that disrupting this process may prevent epilepsy. While experimental models of epileptogenesis have shown that GABAergic drugs, including valproate (VPA), may be antiepileptogenic, the timing of treatment with putative prophylactic drugs has not been studied. Recent laboratory work explored this issue using an in vitro model of posttraumatic epileptogenesis. The data suggest that a limited time domain exists for VPA to intervene in the epileptogenic process, requiring the earliest possible intervention. We contend that protection from posttraumatic epileptogenesis can be conferred only if agents are given soon after trauma. A pilot study is proposed to begin to translate these findings to explore the feasibility of early VPA delivery to severe head trauma patients admitted to Kings County Hospital Center in Brooklyn, NY, a Level 1 trauma center.

Animals↗