Differential and Time-Dependent Changes in Gene Expression for Type II Calcium/Calmodulin-Dependent Protein Kinase, 67 kDa Glutamic Acid Decarboxylase, and Glutamate Receptor Subunits in Tetanus Toxin-Induced Focal Epilepsy

Abstract

To study potential molecular mechanisms of epileptogenesis in the neocortex, the motor cortex of rats was injected with tetanus toxin (TT), and gene expression for 67 kDa glutamic acid decarboxylase (GAD-67), type II calcium/calmodulin-dependent protein kinase (CaMKII), NMDA receptor subunit 1 (NR1), and AMPA receptor subunit 2 (GluR2) was investigated by in situ hybridization histochemistry. Injections of 20-35 ng TT induced recurrent seizures after a postoperative period ranging from 4 to 13 d. A majority of rats perfused 5-7 d after TT injection showed altered gene expression, but the changes varied in their areal extent, ranging from most neocortical areas on the injected side in some rats to mainly the frontoparietal cortex or the motor cortex in others. Epileptic rats perfused 14 d after TT injection showed a focus of increased GAD-67 and NR1, and of decreased alpha-CaMKII and GluR2 mRNA levels at the injection site. A zone of cortex surrounding the focus showed changes in alpha-CaMKII, GAD-67, and NR1 mRNA levels that were reciprocal to those in the focus. The results suggest that TT-induced seizure activity initially spread to a variable extent but was gradually restricted 2-3 d after seizure onset. The focus and the surround showing reciprocal changes in gene expression are thought to correspond to the electrophysiologically identified epileptic focus and inhibitory surround, respectively. The findings suggest that lateral inhibition between neighboring cortical regions will be affected and contribute to a neurochemical segregation of an epileptic focus from surrounding cortex.

Effect of astrocyte‐targeted production of IL‐6 on traumatic brain injury and its impact on the cortical transcriptome

“…Altered calcium homeostasis is one of the features of traumatic injury, leading to excitotoxicity and cell death, both by necrotic and apoptotic mechanisms as well as learning impairment after traumatic injuries (see Won et al, 2002; for review). Furthermore, it is not surprising to find that calcium-related genes are down-regulated after cryolesion as this has been described previously both at at the protein and mRNA level for Calcium-calmodulin dependent protein kinase II (CamKII) after an ischemic insult (Shimada et al, 1998), epilepsy (Liang and Jones, 1997), and in an excitotoxic model in vitro (Churn et al, 1993). In this regard, the gene codifying for the isoform beta from CaMKII (EST, moderately similar to A47643 hypothetical protein-mouse, also known as calcium/calmodulin-dependent protein kinase II, beta-Camk2b-), although slightly increased in WT mice at 1 dpl was remarkably down-regulated in GFAP-IL6 mice at all time points.…”

Glutamate Receptor Subtypes Mediating Synaptic Activation of Prefrontal Cortex Neurons: Relevance for Schizophrenia

“…For example, deprivation of afferent activity decreases GAD67 levels and inhibitory synaptic strength (Benson et al, 1994;Jiao et al, 2006;He et al, 2006). Conversely, cortical network hyperactivity increases GAD67 (Liang and Jones, 1997;Esclapez and Houser, 1999). Interestingly, NMDAR blockade depresses the so-called up-states in vitro (Tu et al, 2007;Kroener et al, 2009) and in vivo (Steriade et al, 1993;Seamans et al, 2003), thus producing network hypoactivity.…”

Prostaglandin E2-Induced Synaptic Plasticity in Neocortical Networks of Organotypic Slice Cultures

“…(1) a change in the state of existing glutamate receptors resulting from phosphorylation (McGlade-McCulloh et al, 1993), (2) an insertion of previously inactive glutamate receptors (AMPA) into the postsynaptic membrane (Newpher and Ehlers, 2008;Kessels and Malinow, 2009), and/or (3) a synthesis of new receptors and insertion in the postsynaptic membrane (Liang and Jones, 1997). However, minianalysis cannot exclude the possibility that TTX caused a presynaptic change in vesicular neurotransmitter content leading to activation of a larger number of receptors.…”