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Patterns of Spontaneous Local Network Activity in Developing Cerebral Cortex: Relationship to Adult Cognitive Function.

Peinado A, Abrams CK - PLoS ONE (2015)

Bottom Line: Our results show significant differences in this activity between strains: compared to a high cognitive-performing strain, we consistently found an increase in frequency and decrease in intensity in neonates from three lower performing strains.Activity was most different in one strain considered a model of schizophrenia-like psychopathology.Our results further suggest that the strength of dopaminergic signaling, by setting the balance between excitation and inhibition, is a potential underlying mechanism that could explain the observed differences in early spontaneous activity patterns.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.

ABSTRACT
Detecting neurodevelopμental disorders of cognition at the earliest possible stages could assist in understanding them mechanistically and ultimately in treating them. Finding early physiological predictors that could be visualized with functional neuroimaging would represent an important advance in this regard. We hypothesized that one potential source of physiological predictors is the spontaneous local network activity prominent during specific periods in development. To test this we used calcium imaging in brain slices and analyzed variations in the frequency and intensity of this early activity in one area, the entorhinal cortex (EC), in order to correlate early activity with level of cognitive function later in life. We focused on EC because of its known role in different types of cognitive processes and because it is an area where spontaneous activity is prominent during early postnatal development in rodent models of cortical development. Using rat strains (Long-Evans, Wistar, Sprague-Dawley and Brattleboro) known to differ in cognitive performance in adulthood we asked whether neonatal animals exhibit corresponding strain-related differences in EC spontaneous activity. Our results show significant differences in this activity between strains: compared to a high cognitive-performing strain, we consistently found an increase in frequency and decrease in intensity in neonates from three lower performing strains. Activity was most different in one strain considered a model of schizophrenia-like psychopathology. While we cannot necessarily infer a causal relationship between early activity and adult cognition our findings suggest that the pattern of spontaneous activity in development could be an early predictor of a developmental trajectory advancing toward sub-optimal cognitive performance in adulthood. Our results further suggest that the strength of dopaminergic signaling, by setting the balance between excitation and inhibition, is a potential underlying mechanism that could explain the observed differences in early spontaneous activity patterns.

No MeSH data available.


Related in: MedlinePlus

GABA-A and D1/D5 dopamine receptors shape the pattern of EC spontaneous activity.Results of experiments comparing EC activity before and during application of the GABA-A antagonist bicuculline (BIC; 10μM) or the D1/D5 antagonist SCH23390 (SCH; 10μM) show the shifts in the pattern of activation towards or away from an LE-like pattern, respectively. The observed changes in event frequency (A), maximal event intensity (B), and overall intensity of activation (C) in EC are consistent with the view that higher excitation drives activity toward the LE pattern, and higher inhibition drives it toward the pattern found in low performing strains. Representative traces and images of calcium-dependent fluorescence obtained before and during SCH application (D) and BIC application (E) illustrate the changes observed. BIC experiments: n = 6 slices from 6 SD pups, ages P5-P9. SCH experiments: n = 6 slices from 6 W pups, ages P4-P6. Orientation in all images: lateral is up, caudal is left. * p<0.05; ** p<0.01 paired t-test of mean values obtained before and during antagonist application in each slice.
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pone.0131259.g005: GABA-A and D1/D5 dopamine receptors shape the pattern of EC spontaneous activity.Results of experiments comparing EC activity before and during application of the GABA-A antagonist bicuculline (BIC; 10μM) or the D1/D5 antagonist SCH23390 (SCH; 10μM) show the shifts in the pattern of activation towards or away from an LE-like pattern, respectively. The observed changes in event frequency (A), maximal event intensity (B), and overall intensity of activation (C) in EC are consistent with the view that higher excitation drives activity toward the LE pattern, and higher inhibition drives it toward the pattern found in low performing strains. Representative traces and images of calcium-dependent fluorescence obtained before and during SCH application (D) and BIC application (E) illustrate the changes observed. BIC experiments: n = 6 slices from 6 SD pups, ages P5-P9. SCH experiments: n = 6 slices from 6 W pups, ages P4-P6. Orientation in all images: lateral is up, caudal is left. * p<0.05; ** p<0.01 paired t-test of mean values obtained before and during antagonist application in each slice.

Mentions: Our results raise the question of what mechanism(s) may underlie the observed correlation between depressed EC activity early in development and low cognitive performance later in life. Altered cortical GABA-A, glutamatergic and dopaminergic neurotransmission have been implicated in the cognitive dysfunction of schizophrenia [28,29,30], and dopaminergic innervation of EC is reduced in the brains of schizophrenics [31]. Any one of these alterations could result in a disturbed balance between excitation and inhibition in the immature EC. (Note that, unlike in the immature hippocampus, where GABA-A is excitatory, GABA-A inhibits action potential firing and associated calcium transients in the immature EC (see S1 Fig), as in all cortical areas outside hippocampus). Therefore, in the third part of this study we investigated the role of GABA-A receptors and dopamine neuromodulation in shaping the pattern of activity in low performing strains (W and SD) by comparing activity before and during application of antagonists to GABA-A and D1 receptors. We evaluated three of the parameters described above: frequency of events, maximal intensity of activity (local measure), and overall intensity of activity (global measure for all EC). Our results show that activity in the presence of the GABA-A antagonist exhibits significant changes in the three parameters, all of which shifted towards a pattern more typical of the Long Evans pattern (Fig 5). The shift resulting from acute antagonist treatment is only partial, suggesting that other mechanisms are involved and/or that changes in the functional properties of the network have already taken place even at these early ages and cannot be reversed, at least in the short timeframe of these experiments. The results are consistent with the notion that a difference in GABA-A-mediated inhibition could account for differences in the three main parameters of spontaneous activation observed between high and low performing strains.


Patterns of Spontaneous Local Network Activity in Developing Cerebral Cortex: Relationship to Adult Cognitive Function.

Peinado A, Abrams CK - PLoS ONE (2015)

GABA-A and D1/D5 dopamine receptors shape the pattern of EC spontaneous activity.Results of experiments comparing EC activity before and during application of the GABA-A antagonist bicuculline (BIC; 10μM) or the D1/D5 antagonist SCH23390 (SCH; 10μM) show the shifts in the pattern of activation towards or away from an LE-like pattern, respectively. The observed changes in event frequency (A), maximal event intensity (B), and overall intensity of activation (C) in EC are consistent with the view that higher excitation drives activity toward the LE pattern, and higher inhibition drives it toward the pattern found in low performing strains. Representative traces and images of calcium-dependent fluorescence obtained before and during SCH application (D) and BIC application (E) illustrate the changes observed. BIC experiments: n = 6 slices from 6 SD pups, ages P5-P9. SCH experiments: n = 6 slices from 6 W pups, ages P4-P6. Orientation in all images: lateral is up, caudal is left. * p<0.05; ** p<0.01 paired t-test of mean values obtained before and during antagonist application in each slice.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4476761&req=5

pone.0131259.g005: GABA-A and D1/D5 dopamine receptors shape the pattern of EC spontaneous activity.Results of experiments comparing EC activity before and during application of the GABA-A antagonist bicuculline (BIC; 10μM) or the D1/D5 antagonist SCH23390 (SCH; 10μM) show the shifts in the pattern of activation towards or away from an LE-like pattern, respectively. The observed changes in event frequency (A), maximal event intensity (B), and overall intensity of activation (C) in EC are consistent with the view that higher excitation drives activity toward the LE pattern, and higher inhibition drives it toward the pattern found in low performing strains. Representative traces and images of calcium-dependent fluorescence obtained before and during SCH application (D) and BIC application (E) illustrate the changes observed. BIC experiments: n = 6 slices from 6 SD pups, ages P5-P9. SCH experiments: n = 6 slices from 6 W pups, ages P4-P6. Orientation in all images: lateral is up, caudal is left. * p<0.05; ** p<0.01 paired t-test of mean values obtained before and during antagonist application in each slice.
Mentions: Our results raise the question of what mechanism(s) may underlie the observed correlation between depressed EC activity early in development and low cognitive performance later in life. Altered cortical GABA-A, glutamatergic and dopaminergic neurotransmission have been implicated in the cognitive dysfunction of schizophrenia [28,29,30], and dopaminergic innervation of EC is reduced in the brains of schizophrenics [31]. Any one of these alterations could result in a disturbed balance between excitation and inhibition in the immature EC. (Note that, unlike in the immature hippocampus, where GABA-A is excitatory, GABA-A inhibits action potential firing and associated calcium transients in the immature EC (see S1 Fig), as in all cortical areas outside hippocampus). Therefore, in the third part of this study we investigated the role of GABA-A receptors and dopamine neuromodulation in shaping the pattern of activity in low performing strains (W and SD) by comparing activity before and during application of antagonists to GABA-A and D1 receptors. We evaluated three of the parameters described above: frequency of events, maximal intensity of activity (local measure), and overall intensity of activity (global measure for all EC). Our results show that activity in the presence of the GABA-A antagonist exhibits significant changes in the three parameters, all of which shifted towards a pattern more typical of the Long Evans pattern (Fig 5). The shift resulting from acute antagonist treatment is only partial, suggesting that other mechanisms are involved and/or that changes in the functional properties of the network have already taken place even at these early ages and cannot be reversed, at least in the short timeframe of these experiments. The results are consistent with the notion that a difference in GABA-A-mediated inhibition could account for differences in the three main parameters of spontaneous activation observed between high and low performing strains.

Bottom Line: Our results show significant differences in this activity between strains: compared to a high cognitive-performing strain, we consistently found an increase in frequency and decrease in intensity in neonates from three lower performing strains.Activity was most different in one strain considered a model of schizophrenia-like psychopathology.Our results further suggest that the strength of dopaminergic signaling, by setting the balance between excitation and inhibition, is a potential underlying mechanism that could explain the observed differences in early spontaneous activity patterns.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.

ABSTRACT
Detecting neurodevelopμental disorders of cognition at the earliest possible stages could assist in understanding them mechanistically and ultimately in treating them. Finding early physiological predictors that could be visualized with functional neuroimaging would represent an important advance in this regard. We hypothesized that one potential source of physiological predictors is the spontaneous local network activity prominent during specific periods in development. To test this we used calcium imaging in brain slices and analyzed variations in the frequency and intensity of this early activity in one area, the entorhinal cortex (EC), in order to correlate early activity with level of cognitive function later in life. We focused on EC because of its known role in different types of cognitive processes and because it is an area where spontaneous activity is prominent during early postnatal development in rodent models of cortical development. Using rat strains (Long-Evans, Wistar, Sprague-Dawley and Brattleboro) known to differ in cognitive performance in adulthood we asked whether neonatal animals exhibit corresponding strain-related differences in EC spontaneous activity. Our results show significant differences in this activity between strains: compared to a high cognitive-performing strain, we consistently found an increase in frequency and decrease in intensity in neonates from three lower performing strains. Activity was most different in one strain considered a model of schizophrenia-like psychopathology. While we cannot necessarily infer a causal relationship between early activity and adult cognition our findings suggest that the pattern of spontaneous activity in development could be an early predictor of a developmental trajectory advancing toward sub-optimal cognitive performance in adulthood. Our results further suggest that the strength of dopaminergic signaling, by setting the balance between excitation and inhibition, is a potential underlying mechanism that could explain the observed differences in early spontaneous activity patterns.

No MeSH data available.


Related in: MedlinePlus