Remodeling of synaptic architecture during hippocampal "kindling".

Abstract

The "kindling" phenomenon is associated with long-lasting facilitation of synaptic transmission. A possible mechanism of such facilitation could involve changes in the number of synaptic contacts. However, previous attempts to demonstrate a synaptic morphological alteration that could account for the long-term effects ofkindling had failed, possibly due to the unavailability, at the time, of unbiased methods for synapse quantitation. Using the unbiased stereological disector technique, we estimated the number of synapses per neuron in the middle molecular layer of the hippocampal dentate gyrus in rats kindled by electrical stimulation of the medial perforant path with implanted electrodes. Unkindled but stimulated (coulodibit control) and unstimulated but implanted rats served as controls. Animals were coded and killed 4 weeks after reaching the kindling criterion of five generalized seizures. The most important results were obtained when axospinous synapses with continuous or discontinuous postsynaptic densities ("nonperforated" or "perforated" synapses) were differentially analyzed. Kindling resulted in a selective loss of nonperforated synaptic contacts in contrast to preservation of perforated ones. Furthermore, the ratio of perforated to nonperforated synapses was increased by 45% or 40% in kindled rats relative to unstimulated or coulombic controls, respectively. These findings suggest that synaptic efficacy may depend on a balance of the two synaptic types; selective elimination of nonperforated synapses may augment the potency ofremaining synaptic contacts, a process reminiscent of synaptic remodeling during development."Kindling" may be viewed as an experimental model of the formation of an engram in the brain (1, 2). It differs from all other models of synaptic plasticity (or neuronal models of memory) by reason of its extraordinary duration. After only a few exposures to a low-level, localized electrical stimulus, the synaptic responsiveness of the stimulated circuit undergoes an augmentation that persists, without further reinforcement, for many months.In the kindling paradigm (3, 4), a subthreshold electrical stimulus is repeatedly delivered to a local brain area once or twice a day for a duration of 1-2 sec. When first applied, the electrical stimulation results in only brief afterdischarge (AD) and no behavioral alteration. Without any change in stimulation parameters, the AD gradually increases in duration and spreads from the stimulated area to increasingly distant, though synaptically connected, brain regions. A progressive alteration of behavior is also seen, beginning with momentary arrest of ongoing locomotor activity and proceeding through localized twitching to a generalized seizure. Once generalized seizures have occurred, cessation of stimulation for weeks, months, or even years does not result in loss of the newly acquired, electrophysiologically and behaviorally defined change (2, 5, 6). Reintroduction of the original stimulus, which was behaviorally ineffective to begin with, ...

Effect of septal kindling on glutamate binding and calcium/calmodulin-dependent phosphorylation in a postsynaptic density fraction isolated from rat cerebral cortex.

“…However, two other groups (76,77) found no significant structural changes in the affected areas of hippocampus between control and kindled animals. The selective loss of nonperforated PSDs seen in hippocampal kindling by Geinisman et al (78)(79)(80), increasing the ratio of perforated to nonperforated PSDs, is quite compatible with our finding of increased glutamate-binding sites. PSDs from cortex (24,81) and hippocampus (22) contain glutamate receptors, the activation of which involves the opening of Na' and Ca2+ channels in the postsynaptic membrane (82)(83)(84).…”

Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma.

“…NGF can stimulate sprouting of cholinergic axons in the adult rat cerebral cortex and hippocampus (8,48). Furthermore, in rats subjected to repeated seizures by electrical kindling stimulations, which lead to increased levels of mRNA for NGF and BDNF (32), sprouting of mossy fibers and formation of aberrant synaptic contacts have been found in the hippocampus (49)(50)(51)(52). Increased production of neurotrophic factors might also constitute a protective mechanism ameliorating brain damage after ischemia and hypoglycemia, particularly neuronal necrosis of the delayed type, which develops over several days Neurobiology: Lindvall et al…”

Synaptic Elimination, Neurodevelopment, and the Mechanism of Hallucinated “Voices” in Schizophrenia

“…The pruning procedure was guided by the concept of neurodevelopmental "Darwinism," where neurons compete with each other for anatomic access to other neurons, with elimination of less robust interneuron connections (37)(38)(39). In mathematical terms, if the absolute value of a connection weight linking the temporary and hidden layers was below a certain threshold, it was "clamped" at 0.…”