Involvement of a Glutamatergic Mechanism in δ‐Dendrotoxin‐Induced Hippocampal Neuronal Cell Loss in the Rat

Abstract

Abstract:The epileptogenic and neurodegenerative effects of d-dendrotoxin, from Dendroaspis angusticeps, a specific blocker of a non-inactivating, voltage-sensitive K π channel, were studied after focal injection into one dorsal hippocampus in rats pretreated with CGP040116, a N-methyl-D-aspartate (NMDA) receptor antagonist, and in rats bearing a monolateral surgical lesion of the Schaffer collaterals whose terminals originate from CA3 pyramids and release glutamate in the CA1 hippocampal area. Administration of 35 pmol d-dendrotoxin elicited in all of the treated animals (nΩ8) bilateral EEG discharges and damage to the hippocampal formation. Quantitation of the damage revealed significant bilateral neuronal cell loss in the CA1, CA3 and CA4 pyramidal cell layers. The lowest dose (0.35 pmol; nΩ4) of the toxin used did not affect EEG activity and failed to cause significant hippocampal cell loss whereas the 3.5 pmol (nΩ6) dose caused EEG seizures and hippocampal cell loss limited to the CA1 area. Systemic intraperitoneal administration of CGP040116 (5 mg/ kg given 30 min. previously) delayed the onset of EEG seizures and reduced the number of epileptogenic discharges typically observed in rats receiving an injection of d-dendrotoxin (35 pmol) alone. Similarly, this treatment prevented the damage inflicted to the hippocampus by the toxin and in no instance was significant neuronal loss observed. Protection against seizures and hippocampal damage was also observed by a monolateral surgical lesion to the Schaffer collaterals.In conclusion, the present data suggest that an excitotoxic, glutamate-mediated, type of mechanism underlies seizures and hippocampal damage induced by d-dendrotoxin in rats.

Differential modulation of repetitive firing and synchronous network activity in neocortical interneurons by inhibition of A-type K+ channels and Ih

“…Kv3.2 channels are also highly expressed in non-fast-spiking SOM positive interneurons in the neocortex, where they may play a different role in repetitive firing ( Weiser et al, 1994 ; Chow et al, 1999 ). Consistent with their role in regulating intrinsic excitability, the genetic loss or pharmacological blockade of A-type K + channels is epileptogenic ( Smart et al, 1998 ; Avoli et al, 2001 ; Bagetta et al, 2004 ; Monaghan et al, 2008 ). It remains unclear how the inhibition of A-type K + channels induces interneuron synchronization.…”

Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy

“…In the mammalian hippocampus, Kv1.1 and Kv1.4 α subunits are highly expressed in nerve terminals of the perforant path, mossy fiber, and Schaffer collateral pathways (Sheng et al, 1992, Wang et al, 1993, Wang et al, 1994, Maletic-Savatic et al, 1995, Rhodes et al, 1997, Monaghan et al, 2001), while Kv4.2 α subunits and associated KChIPs are expressed at high levels in the dendrites of dentate granule cells, and of CA3 and CA1 pyramidal cells (Sheng et al, 1992, Maletic-Savatic et al, 1995, Varga et al, 2000, Rhodes et al, 2004). Pharmacological blockade of presynaptic Kv1 channels (Bagetta et al, 2004), or genetic ablation of Kv1.1 expression in mice (Smart et al, 1998) is epileptogenic, as is pharmacological blockade of somatodendritic Kv4 channels (Avoli, 2001). Importantly, a recent study shows that the amplitude of backpropagating action potentials is increased in CA1 pyramidal cell dendrites in pilocarpine-induced TLE, suggesting decreased functional expression of dendritic Kv4 channels (Bernard et al, 2004).…”

Structural characterization of PPTI, a kunitz-type protein from the venom of Pseudocerastes persicus

“…On the other hand, DTXs act as a facilitator of neurotransmitter release from pre-synaptic neurons by blocking ionic current in voltage-gated potassium channels (Kv) [1,9,14–16]. For an effective interaction with Kv channels, a basic residue of DTXs interacts with both negatively charged (E353 and D431 in Kv1.1) and aromatic residues (Y379 in Kv1.1) of the pore region in Kv channels [11,17,18]. According to site-directed mutagenesis studies, this basic residue along with a hydrophobic residue are mostly responsible in making interactions with Kv channels, and simultaneous mutations of these two residues cause a great reduction (about 1000 times) in DTXs function against Kv channels [1,12].…”

“…According to site-directed mutagenesis studies, this basic residue along with a hydrophobic residue are mostly responsible in making interactions with Kv channels, and simultaneous mutations of these two residues cause a great reduction (about 1000 times) in DTXs function against Kv channels [1,12]. In addition, the configuration of functional sites in DTX variants is in a way that the critical basic residue protrudes from the functional surface [11] and keeps a certain distance (about 6.6±1 Å) from the hydrophobic residue [17,18].…”