Neuroscience
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Comparative Study
Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus.
Prior studies showed that positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators facilitate long-term potentiation (LTP) and improve the formation of several types of memory in animals and humans. However, these modulators are highly diverse in their effects on receptor kinetics and synaptic transmission and thus may differ also in their efficacy to promote changes in synaptic strength. The present study examined three of these modulators for their effects on synaptic plasticity in field CA1 of hippocampal slices, two of them being the benzamide drugs 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) which prominently enhance synaptic transmission yet differ in their relative impact on amplitude versus duration of the synaptic response. ⋯ Tests with recombinant NMDA receptors (NR1/NR2A) showed that CX516 and CX546 have no direct effects on currents mediated by these receptors. These results suggest that (1) modulation of AMPA receptors which increases either response amplitude or duration can facilitate LTP formation, (2) modulators that effectively slow response deactivation augment the maximum magnitude of LTP and LTD, and (3) receptor desensitization may have a minor impact on synaptic plasticity in the hippocampus. Taken together, our data indicate that AMPA receptor modulators differ substantially in their ability to enhance synaptic potentiation or depression, depending on their particular influence on receptor kinetics, and hence that they may also be differentially effective in influencing higher-order processes such as memory encoding.
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During development norepinephrine plays a role in determining the morphologic organization of the CNS and the density and future responsiveness of adrenergic receptors. alpha-2 Adrenergic receptors, one of three adrenergic receptor types, regulate important adult CNS functions and may have a distinct role during development. We examined alpha-2 receptor distribution and density in the rat brain at postnatal days 1, 5, 10, 15, 21, 28 and in adults using the antagonist [(3)H]RX821002 for autoradiography. Binding kinetics and pharmacology for alpha-2 adrenergic receptors were the same in adults and neonates. ⋯ Third, some regions demonstrated decreasing or transient expression of alpha-2 adrenergic receptors in the course of postnatal development, including white matter regions, cerebellum and many brainstem nuclei, suggesting specific roles for alpha-2 receptors during development. This study investigates the development of alpha-2 adrenergic receptors in the rat CNS. It demonstrates there is region-specific regulation of alpha-2 receptor development and identifies brain regions where these receptors may play a specific and critical role in the regulation normal development.
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Comparative Study
The hypothalamic-pituitary-adrenal and glucose responses to daily repeated immobilisation stress in rats: individual differences.
It is accepted that there are important individual differences in the vulnerability to stress-induced pathologies, most of them associated to the hypothalamic-pituitary and sympatho-medullo-adrenal axes, the two prototypical stress-responsive systems. However, there are few studies specifically aimed at characterising individual differences in the physiological response to daily repeated stress in rats. In the present work, male rats were submitted to repeated immobilisation (IMO) stress (1 h daily for 13 days) and several samples were taken at specific days and time points. ⋯ When the animals were classified in three groups on the basis of their plasma ACTH levels immediately after the first immobilisation, individual differences in the ACTH response progressively disappeared on successive exposures to the stressor, whereas those in corticosterone and glucose were more sustained. The present results suggest that there are individual differences in the physiological response to stress that tend to be reduced rather than accentuated by repeated exposure to the stressor. Nevertheless, this buffering effect of repeated stress was dependent on the particular variable studied.
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Comparative Study
Developmental expression of methyl-CpG binding protein 2 is dynamically regulated in the rodent brain.
The gene encoding methyl-CpG binding protein 2 (MeCP2) is mutated in the large majority of girls that have Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. To better understand the developmental role of MeCP2, we studied the ontogeny of MeCP2 expression in rat brain using MeCP2 immunostaining and Western blots. MeCP2 positive neurons were present throughout the brain at all ages examined, although expression varied by region and age. ⋯ The timing of MeCP2 expression in the granule cell layer is coincident with the onset of granule cell synapse formation. Although more subtle, the degree of MeCP2 expression in cortex and hippocampus was most closely correlated with synaptogenesis in both regions. Our finding that MeCP2 expression is correlated with synaptogenesis is consistent with the hypothesis that Rett Syndrome is caused by defects in the formation or maintenance of synapses.
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To help discern sites of focal activation during seizures of different phenotype, the numbers of Fos immunoreactive (FI) neurons in specific brain regions were analyzed following "brainstem-evoked," "forebrain-evoked" and forebrain/brainstem combination seizures induced by a variety of methods. First, pentylenetetrazol (PTZ, 50 mg/kg) induced forebrain-type seizures in some rats, or forebrain seizures that progressed to tonic/clonic brainstem-type seizures in other rats. Second, minimal electroshock induced forebrain seizures whereas maximal electroshock (MES) induced tonic brainstem-type seizures in rats. ⋯ These findings suggest these latter areas may be transitional areas between forebrain and brainstem seizure interactions. Collectively, these data illustrate a generally consistent pattern of forebrain Fos staining associated with forebrain-type seizures and a consistent pattern of brainstem Fos staining associated with brainstem-type seizures. Additionally, these data are consistent with a notion that separate seizure circuitries in the forebrain and brainstem mutually interact to facilitate one another, possibly through involvement of specific "transition mediating" nuclei.