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Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation.

Smucny J, Stevens KE, Olincy A, Tregellas JR - Transl Psychiatry (2015)

Bottom Line: We show that drug effects on the P20-N40 are highly predictive of human effects across similar dose ranges.Furthermore, mental status (for example, anesthetized vs alert) does not appear to diminish the predictive capacity of these recordings.We then discuss hypothesized neuropharmacologic mechanisms that may underlie gating effects for each drug studied.

View Article: PubMed Central - PubMed

Affiliation: 1] Neuroscience Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA [2] Research Service, Denver VA Medical Center, Denver, CO, USA [3] Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

ABSTRACT
Impaired gating of the auditory evoked P50 potential is one of the most pharmacologically well-characterized features of schizophrenia. This deficit is most commonly modeled in rodents by implanted electrode recordings from the hippocampus of the rodent analog of the P50, the P20-N40. The validity and effectiveness of this tool, however, has not been systematically reviewed. Here, we summarize findings from studies that have examined the effects of pharmacologic modulation on gating of the rodent hippocampal P20-N40 and the human P50. We show that drug effects on the P20-N40 are highly predictive of human effects across similar dose ranges. Furthermore, mental status (for example, anesthetized vs alert) does not appear to diminish the predictive capacity of these recordings. We then discuss hypothesized neuropharmacologic mechanisms that may underlie gating effects for each drug studied. Overall, this review supports continued use of hippocampal P20-N40 gating as a translational tool for schizophrenia research.

No MeSH data available.


Related in: MedlinePlus

Representative P50 event-related potentials illustrating P50 gating deficits in schizophrenia. (a) In a healthy subject (left pair of traces), the brain inhibits its response to the second (S2) of a pair of repeated stimuli. A patient with schizophrenia (right pair of traces) is unable to inhibit response to this stimulus. (b) This effect can be normalized by treatments that increase response to the first stimulus (S1, left pair of traces) or decrease response to second stimulus (S2, right pair of traces). S1, first stimulus; S2, second stimulus; SZ, schizophrenia.
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fig1: Representative P50 event-related potentials illustrating P50 gating deficits in schizophrenia. (a) In a healthy subject (left pair of traces), the brain inhibits its response to the second (S2) of a pair of repeated stimuli. A patient with schizophrenia (right pair of traces) is unable to inhibit response to this stimulus. (b) This effect can be normalized by treatments that increase response to the first stimulus (S1, left pair of traces) or decrease response to second stimulus (S2, right pair of traces). S1, first stimulus; S2, second stimulus; SZ, schizophrenia.

Mentions: The ‘hypervigilant' state found in schizophrenia led Adler et al.10 to postulate that patients may show a deficit in the ability of the brain to physiologically decrease, or ‘gate,' its response to repeated stimuli. This brain response is postulated to have a major role in the ability of healthy subjects to subconsciously ignore irrelevant, incessant stimuli in the environment such as a clock ticking.9 On the basis of electroencephalographic methods developed in the 1960s for studying repetitive auditory stimuli,11 Adler et al.10 observed reduced capacity in schizophrenia to diminish early (50 ms post stimulus, or P50) responses to the second of a pair closely spaced identical (~0.5 s) clicks (Figure 1a). This phenomenon has since been replicated in many laboratories, is predictive of cognitive function in several domains including attention12, 13, 14, 15 and is one of the most frequently investigated electrophysiological phenotypes in schizophrenia. The relationships between P50 gating and positive and negative symptomatology are unclear and an important area for future investigation (reviewed by Potter et al.13). As discussed later in this review, studies have found that this phenotype can be normalized by a number of compounds, either by increasing the physiological response to the first click (relative to the second) and/or decreasing the response to the second click (relative to the first; Figure 1b).


Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation.

Smucny J, Stevens KE, Olincy A, Tregellas JR - Transl Psychiatry (2015)

Representative P50 event-related potentials illustrating P50 gating deficits in schizophrenia. (a) In a healthy subject (left pair of traces), the brain inhibits its response to the second (S2) of a pair of repeated stimuli. A patient with schizophrenia (right pair of traces) is unable to inhibit response to this stimulus. (b) This effect can be normalized by treatments that increase response to the first stimulus (S1, left pair of traces) or decrease response to second stimulus (S2, right pair of traces). S1, first stimulus; S2, second stimulus; SZ, schizophrenia.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490287&req=5

fig1: Representative P50 event-related potentials illustrating P50 gating deficits in schizophrenia. (a) In a healthy subject (left pair of traces), the brain inhibits its response to the second (S2) of a pair of repeated stimuli. A patient with schizophrenia (right pair of traces) is unable to inhibit response to this stimulus. (b) This effect can be normalized by treatments that increase response to the first stimulus (S1, left pair of traces) or decrease response to second stimulus (S2, right pair of traces). S1, first stimulus; S2, second stimulus; SZ, schizophrenia.
Mentions: The ‘hypervigilant' state found in schizophrenia led Adler et al.10 to postulate that patients may show a deficit in the ability of the brain to physiologically decrease, or ‘gate,' its response to repeated stimuli. This brain response is postulated to have a major role in the ability of healthy subjects to subconsciously ignore irrelevant, incessant stimuli in the environment such as a clock ticking.9 On the basis of electroencephalographic methods developed in the 1960s for studying repetitive auditory stimuli,11 Adler et al.10 observed reduced capacity in schizophrenia to diminish early (50 ms post stimulus, or P50) responses to the second of a pair closely spaced identical (~0.5 s) clicks (Figure 1a). This phenomenon has since been replicated in many laboratories, is predictive of cognitive function in several domains including attention12, 13, 14, 15 and is one of the most frequently investigated electrophysiological phenotypes in schizophrenia. The relationships between P50 gating and positive and negative symptomatology are unclear and an important area for future investigation (reviewed by Potter et al.13). As discussed later in this review, studies have found that this phenotype can be normalized by a number of compounds, either by increasing the physiological response to the first click (relative to the second) and/or decreasing the response to the second click (relative to the first; Figure 1b).

Bottom Line: We show that drug effects on the P20-N40 are highly predictive of human effects across similar dose ranges.Furthermore, mental status (for example, anesthetized vs alert) does not appear to diminish the predictive capacity of these recordings.We then discuss hypothesized neuropharmacologic mechanisms that may underlie gating effects for each drug studied.

View Article: PubMed Central - PubMed

Affiliation: 1] Neuroscience Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA [2] Research Service, Denver VA Medical Center, Denver, CO, USA [3] Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

ABSTRACT
Impaired gating of the auditory evoked P50 potential is one of the most pharmacologically well-characterized features of schizophrenia. This deficit is most commonly modeled in rodents by implanted electrode recordings from the hippocampus of the rodent analog of the P50, the P20-N40. The validity and effectiveness of this tool, however, has not been systematically reviewed. Here, we summarize findings from studies that have examined the effects of pharmacologic modulation on gating of the rodent hippocampal P20-N40 and the human P50. We show that drug effects on the P20-N40 are highly predictive of human effects across similar dose ranges. Furthermore, mental status (for example, anesthetized vs alert) does not appear to diminish the predictive capacity of these recordings. We then discuss hypothesized neuropharmacologic mechanisms that may underlie gating effects for each drug studied. Overall, this review supports continued use of hippocampal P20-N40 gating as a translational tool for schizophrenia research.

No MeSH data available.


Related in: MedlinePlus