Balance of Inhibitory and Excitatory Synaptic Activity Is Altered in Fast-Spiking Interneurons in Experimental Cortical Dysplasia

Abstract

Cortical dysplasia (CD) is a common cause of intractable epilepsy in children and adults. We have studied rats irradiated in utero as a model of CD to better understand mechanisms that underlie dysplasia-associated epilepsy. Prior studies have shown a reduction in the number of cortical interneurons and in the frequency of inhibitory postsynaptic currents (IPSCs) in pyramidal cells in this model. They have also shown a reduced frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) in the surviving cortical interneurons. However, the inhibitory synaptic contacts were not examined in that study. The current experiments were performed to assess inhibitory synaptic activity in fast-spiking (FS) interneurons in irradiated rats and controls and the balance of excitatory and inhibitory synaptic activity in these cells. Whole cell recordings were obtained from layer IV FS cells in controls and comparable FS cells in irradiated rats. The frequency of spontaneous and miniature IPSCs was reduced in dysplastic cortex, but the amplitude of these currents was unchanged. Stimulus-evoked IPSCs showed short-term depression in control and short-term facilitation in dysplastic cortex. Simultaneous recording of spontaneous EPSCs and IPSCs showed a shift in the ratio of excitation-to-inhibition in favor of inhibition in FS cells from dysplastic cortex. The same shift toward inhibition was seen when miniature EPSCs and IPSCs were examined. These results show that FS cells in dysplastic cortex have a relative lack of excitatory drive. This may result in an important class of inhibitory cells that are less able to perform their normal function especially in periods of increased excitatory activity.

Presynaptic Inhibitory Terminals Are Functionally Abnormal in a Rat Model of Posttraumatic Epilepsy

“…Significant changes in presynaptic function have been reported in models of temporal lobe epilepsy, including a shift from PPD to PPF for inhibitory postsynaptic potentials (IPSPs) in dentate gyrus granule cells of rats with pilocarpine-induced temporal lobe epilepsy (Kobayashi and Buckmaster 2003), and decreased quantal release of GABA, associated with reduced synaptic vesicle density in both pilocarpine and kainate models of temporal lobe epilepsy (Hirsch et al 1999). A similar shift from PPD to facilitation was reported in IPSCs evoked in layer IV FS cells in the irradiated model of cortical dysplasia (Zhou et al 2009). …”

Plasticity of spontaneous excitatory and inhibitory synaptic activity in morphologically defined vestibular nuclei neurons during early vestibular compensation

“…Furthermore, in other sensory systems, the response of morphologically defined neuron subsets to deafferentation depends on their role in the network (e.g., Francis and Manis 2000;Li et al 2009;Zhou et al 2009). Accordingly, here we propose that the vestibular nuclei neuron subsets selected for study should be distinguished by key morphological features, including axonal output, neurotransmitter phenotype, and/or neuron morphology and that these subsets should be analyzed as separate independent groups after peripheral vestibular lesions.…”

TRPC3 mediates hyperexcitability and epileptiform activity in immature cortex and experimental cortical dysplasia

“…Our previous histological studies have demonstrated the loss of both interneurons (Deukmedjian et al 2004;Roper et al 1999;Zhou andRoper 2010, 2011) and GABAergic presynaptic terminals (Zhou and Roper 2010) and an increase of the density of glutamatergic terminals in dysplastic cortex (Zhou and Roper 2010). Electrophysiological studies have further confirmed an imbalance between excitatory and inhibitory synaptic inputs to pyramidal neurons (Chen and Roper 2003;Zhu and Roper 2000) and to GABAergic interneurons in irradiated rats with CD (Xiang et al 2006;Zhou et al 2009a;. The imbalance favors inhibition to result in a decreased excitability in interneurons ; in contrast, it favors excitation to result in an increased excitability in pyramidal neurons (Zhu and Roper 2000).…”

“…Immunofluorescence staining was performed as previously described (Zhou et al 2009a(Zhou et al , 2009b. Coronal cortical sections (45 m) were incubated with rabbit anti-TRPC3 polyclonal antibody (2 g/ml; Alomone Labs, Jerusalem, Israel) at 4°C for 72 h and with Alexa Fluor 488 goat anti-rabbit IgG (1:500; Molecular Probes, Invitrogen) for 2.5 h at ϳ23°C.…”