Long-lasting Plastic Changes Research Articles

Structural and functional remodeling in the retina of a mouse with a photoreceptor synaptopathy: plasticity in the rod and degeneration in the cone system

Knowledge about the plastic and regenerative capacity of the retina is of key importance for therapeutic approaches to restore vision in patients who suffer from degenerative retinal diseases. In the retinae of mice, mutant for the presynaptic scaffolding protein Bassoon, signal transfer at photoreceptor ribbon synapses is disturbed due to impaired ribbon attachment to the active zone. In a long-term study we observed, with light and electron microscopic immunocytochemistry and electroretinographic recordings, two overlapping events in the Bassoon mutant retina, i.e. loss of photoreceptor synapses in the outer plexiform layer, and structural remodeling and formation of ectopic photoreceptor synapses in the outer nuclear layer, a region usually devoid of synapses. Formation of ectopic synaptic sites starts around the time when photoreceptor synaptogenesis is completed in wild-type mice and progresses throughout life. The result is a dense plexus of ectopic photoreceptor synapses with significantly altered but considerable synaptic transmission. Ectopic synapse formation is led by the sprouting of horizontal cells followed by the extension of rod bipolar cell neurites that fasciculate with and grow along the horizontal cell processes. Although only the rod photoreceptors and their postsynaptic partners show structural and functional remodeling, our study demonstrates the potential of the retina for long-lasting plastic changes.

Extrasynaptic GABA and Glutamate Receptors in Epilepsy

Epilepsy is a neurological disorder in which normal brain function is disrupted as a consequence of intensive and synchronous burst activity from neuron assemblies. Epilepsies result from long-lasting plastic changes in the brain affecting neurotransmitter release, the properties of receptors and channels, synaptic reorganization and astrocyte activity. There is considerable evidence for alterations in glutamatergic and GABAergic synaptic transmission in the origin of the paroxysmal depolarization shifts that initiate epileptic activity. However, recent studies on non-synaptic transmission, receptor mobility and glia-neuron signaling pathways suggest that extrasynaptic GABA and glutamate receptors may play an important role in seizure initiation, maintenance and arrest. Extracellular aminoacids such as glutamate, aspartate, glycine and GABA seem to communicate neurons and glial cells acting primarily on extrasynaptic receptors. Synaptic and extrasynaptic glutamate and GABA receptors have been show to play different roles in neuronal excitability. NMDA and GABAA receptors expressed in a single neuron can be differentially regulated based on subcellular localization, and it has been proposed that distinct regulation of synaptic versus extrasynaptic receptors provides a mechanism for receptor adaptation in response to a variety of stimuli. Furthermore, glutamate and GABA receptors are highly mobile, and the number and composition of extrasynaptic receptors can be modulated by several factors. This review addresses recent advances in our understanding of the role of extrasynaptic receptors in epilepsy, suggesting that extrasynaptic receptors and their mechanisms of regulation are expected to be important pharmacological targets.

Plastic Corticostriatal Circuits for Action Learning

Reentrant corticobasal ganglia circuits are important for voluntary action and for action selection. In vivo and ex vivo studies show that these circuits can exhibit a plethora of short- and long-lasting plastic changes. Convergent evidence at the molecular, cellular, and circuit levels indicates that corticostriatal circuits are involved in the acquisition and automatization of novel actions. There is strong evidence that activity in corticostriatal circuits changes during the learning of novel actions, but the plastic changes observed during the early stages of learning a novel action are different than those observed after extensive training. A variety of studies indicate that the neural mechanisms and the corticostriatal subcircuits involved in the initial acquisition of actions and skills differ from those involved in their automatization or in the formation of habits. Dopamine, a critical modulator of short- and long-term plasticity in corticostriatal circuits, is differentially involved in early and late stages of action learning. Changes in dopaminergic transmission have several concomitant effects in corticostriatal function, which may be important for action selection and action learning. These diverse effects may subserve different roles for dopamine in reinforcement and action learning.

Induction of LTP in the human auditory cortex by sensory stimulation

High-frequency, repetitive, auditory stimulation was used to determine whether induction of a long-lasting increase of the human auditory evoked potential (AEP) was possible. Recording non-invasively with electroencephalogram scalp electrodes, stable increases in amplitude were observed in the N1 component of the AEP, which is thought to reflect activity within auditory cortex (N1). The increase was maintained over an hour and was shown to be independent of alterations in the state of arousal. This is the first demonstration of the induction of long-lasting plastic changes in AEPs, and suggest that this represents the first direct demonstration of long-term potentiation in the auditory cortex of normal, intact humans.

Kindled seizures increase metabotropic glutamate receptor expression and function in the rat supraoptic nucleus.

The spread of experimentally kindled seizures in rats results in sustained increases in plasma vasopressin (VP) and VP mRNA in the supraoptic nucleus (SON). These increases provide an excellent example of the pathological plasticity that can develop in normal cells exposed to recurrent seizure activity. To test whether this plasticity might be due in part to changes in metabotropic glutamate receptors (mGluRs), we examined mGluR mRNA expression in the SON 1 month after stage 5 amygdala kindling. Three mGluR subtypes were detected by in situ hybridization in the SON in the following relative levels: mGluR3 > mGluR1 > mGluR7. Both mGluR1 and mGluR3 mRNAs were significantly increased in the SON (+28-61%) and cortex (+27-42%) after kindling. Immunoreactivity for mGluR1 but not mGluR2/3 was significantly increased in vivo in the SON. Receptor protein expression and intracellular calcium accumulation in response to the mGluR agonist, 1S,3R ACPD, were evaluated after in vitro "kindling" of neuroendocrine cells by Mg2+ deprivation. Increased immunoreactivity for mGluR1 and mGluR2/3 was seen in all cultures 3 days after a brief exposure to Mg2+-free medium. 1S,3R 1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) induced rapid peak responses and gradual accumulations of intracellular Ca2+ in neurons. Both responses were increased in the "kindled" cells. Increases in the expression of functional mGluR1 and perhaps mGluR3 receptors may contribute to the development of long-lasting plastic changes associated with seizure activity.

Kindled seizures increase metabotropic glutamate receptor expression and function in the rat supraoptic nucleus

The spread of experimentally kindled seizures in rats results in sustained increases in plasma vasopressin (VP) and VP mRNA in the supraoptic nucleus (SON). These increases provide an excellent example of the pathological plasticity that can develop in normal cells exposed to recurrent seizure activity. To test whether this plasticity might be due in part to changes in metabotropic glutamate receptors (mGluRs), we examined mGluR mRNA expression in the SON 1 month after stage 5 amygdala kindling. Three mGluR subtypes were detected by in situ hybridization in the SON in the following relative levels: mGluR3 > mGluR1 > mGluR7. Both mGluR1 and mGluR3 mRNAs were significantly increased in the SON (+28–61%) and cortex (+27–42%) after kindling. Immunoreactivity for mGluR1 but not mGluR2/ 3 was significantly increased in vivo in the SON. Receptor protein expression and intracellular calcium accumulation in response to the mGluR agonist, 1S,3R ACPD, were evaluated after in vitro “kindling” of neuroendocrine cells by Mg2+ deprivation. Increased immunoreactivity for mGluR1 and mGluR2/ 3 was seen in all cultures 3 days after a brief exposure to Mg2+-free medium. 1S,3R 1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) induced rapid peak responses and gradual accumulations of intracellular Ca2+ in neurons. Both responses were increased in the “kindled” cells. Increases in the expression of functional mGluR1 and perhaps mGluR3 receptors may contribute to the development of long-lasting plastic changes associated with seizure activity. J. Neurosci. Res. 54:412–423, 1998. © 1998 Wiley-Liss, Inc.

Activation of spinal N-methyl- d-aspartate or neurokinin receptors induces long-term potentiation of spinal C-fibre-evoked potentials in spinalized rats

The use-dependent increase in synaptic strength between primary afferent C-fibres and second-order neurons in superficial spinal dorsal horn may be an important cellular mechanism underlying central hyperalgesia. This long-term potentiation can be blocked by antagonists of the N-methyl- d-aspartate subtype of glutamate receptor, the neurokinin 1 or the neurokinin 2 receptor. We have tested here whether activation of these receptors by superfusion of the spinal cord with corresponding agonists in the absence of presynaptic activity is sufficient to induce long-term potentiation. In urethane anaesthetized rats C-fibre-evoked field potentials were elicited in superficial laminae of lumbar spinal cord by electrical stimulation of the sciatic nerve. In rats with intact spinal cord, controlled superfusion of the spinal cord at recording segments for 60 min with N-methyl- d-aspartate, substance P or neurokinin A never induced long-term potentiation. Spinal superfusion with a mixture of N-methyl- d-aspartate, substance P and neurokinin A also failed to induce long-term potentiation in four rats tested. In spinalized rats, however, long-term potentiation was induced by either N-methyl- d-aspartate (at 10 μM, to 173±16% of control) substance P (at 10 μM, to 176±13% of control) or by neurokinin A (at 1 μM, to 198±.20% of control). The induction of long-term potentiation by N-methyl- d-aspartate, substance P or neurokinin A was blocked by intravenous application of the receptor antagonists dizocilpine maleate (0.5 mg/kg), RP67580 (2 mg/kg) or SR48968 (0.2 mg/kg), respectively. Thus, activation of N-methyl- d-aspartate or neurokinin receptors may induce long-lasting plastic changes in synaptic transmission in afferent C-fibres and this effect may be prevented by tonic descending inhibition.

MRNA Differential Display RevealsKrox-20 as a Neural Plasticity-Regulated Gene in the Rat Hippocampus

The prolonged maintenance of hippocampal long-term potentiation depends onde novoprotein and RNA synthesis, indicating an involvement of altered gene expression in long-lasting plastic changes in synaptic efficacy. We have used an mRNA differential display technique to identify a set of genes that are induced by neural activity in the rat hippocampus. Sixteen independent cDNAs were isolated whose mRNA level was markedly modulated by convulsive seizure. One of these encodes Krox-20, a zinc finger DNA binding protein. High frequency tetanic stimulation of perforant pathway, which elicited a persistent long-term potentiation (>10 h), rapidly induced expression ofkrox-20 mRNA in the hippocampus of urethane-anesthetized rat. The increase inkrox-20 mRNA was transient and NMDA receptor-dependent. These results suggest a role forkrox-20 in the maintenance of long-term potentiation.

Absence of long-term potentiation in the subcortically deafferented dentate gyrus

All subcortical afferents to the dorsal hippocampus, running in the fimbria-fornix and supracallosal path, were removed by aspiration. Three to 5 months later the rats were implanted with chronic recording electrodes in the dentate gyrus and CA1 region, and stimulating electrodes in the angular bundle. In non-lesioned rats, high-frequency trains delivered to the angular bundle gave rise to a sustained increase of the evoked population spike in the dentate gyrus. In lesioned animals, high-frequency stimulation resulted in only short-lasting changes, and by 15 min after the conditioning trains the amplitude of both the population spike and field postsynaptic potentials returned to baseline. In lesioned rats large amplitude interictal spikes (< 40 ms, 3–8 mV) occurred spontaneously. These findings suggest that either (1) coactivation of entorhinal and subcortical inputs is essential for the induction of long-lasting plastic changes in the dentate gyrus, or (2) the long-term potentiation mechanism is saturated by the chronically occurring interictal discharges in the subcortically denervated dentate gyrus.