Limits...
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

Cartoon schematic of the hypothesized neuronal circuit responsible for sensory gating and its deficits in schizophrenia. Waveform positive polarity is upwards. (a) In a healthy subject, a sound stimulus excites Neuron 1 (for example, the perforant path (PP) input to the hippocampus), which in turn excites hippocampal pyramidal Neuron 3. Neuron 1 also excites inhibitory Neuron 2. (b) Neuron 2 reduces glutamate release by Neuron 1 via activation of presynaptic GABA-B receptors (slow inhibition) as well as inhibits Neuron 3 via activation of postsynaptic GABA-A receptors (fast inhibition). (c) Step 3: a second sound stimulus arrives 500 ms later and excites Neuron 1. Unlike the previous stimulus, Neuron 1 cannot excite Neuron 3 owing to persistent (slow) inhibition from Neuron 2. Signal from the second stimulus is, therefore, reduced or ‘gated.' (d) In a patient with schizophrenia, gating deficits may arise from reduced GABAergic signaling caused by dysfunction of Neuron 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4490287&req=5

fig2: Cartoon schematic of the hypothesized neuronal circuit responsible for sensory gating and its deficits in schizophrenia. Waveform positive polarity is upwards. (a) In a healthy subject, a sound stimulus excites Neuron 1 (for example, the perforant path (PP) input to the hippocampus), which in turn excites hippocampal pyramidal Neuron 3. Neuron 1 also excites inhibitory Neuron 2. (b) Neuron 2 reduces glutamate release by Neuron 1 via activation of presynaptic GABA-B receptors (slow inhibition) as well as inhibits Neuron 3 via activation of postsynaptic GABA-A receptors (fast inhibition). (c) Step 3: a second sound stimulus arrives 500 ms later and excites Neuron 1. Unlike the previous stimulus, Neuron 1 cannot excite Neuron 3 owing to persistent (slow) inhibition from Neuron 2. Signal from the second stimulus is, therefore, reduced or ‘gated.' (d) In a patient with schizophrenia, gating deficits may arise from reduced GABAergic signaling caused by dysfunction of Neuron 2.

Mentions: A remarkable aspect of P50 gating is the simplicity behind the neuronal circuitry that may underlie the phenomenon.16 In its most basic form, this process can be accomplished with only three neurons: two excitatory neurons and an intermediate inhibitory neuron (Figure 2). In the paired-click paradigm, the first, ‘conditioning' stimulus (S1) excites Neuron 1, which in turn excites inhibitory Neuron 2 and excitatory pyramidal Neuron 3 (Figure 2a). Activation of Neuron 2, in turn, induces release of the inhibitory neurotransmitter GABA. GABA release causes fast inhibition of Neuron 3 via postsynaptic GABA-A receptors as well as slow, persistent inhibition of glutamate release onto Neuron 3 from Neuron 1 (via presynaptic GABA-B receptors17). Persistent inhibition in particular diminishes the response of Neuron 3 for up to 8 s (Figure 2b).9 Consequently, if the second, ‘test' stimulus (S2) arrives <1 s after S1, S2 event-related potential amplitude is reduced compared with S1 (Figure 2c). A reduction of the ability of Neuron 2 to modulate this circuit (for example, by reduced α7 nicotinic receptor expression on inhibitory Neuron 2) is postulated to underlie gating deficits in schizophrenia (Figure 2d).16 These deficits are maximal when stimuli are spaced 0.5 s apart, as typically presented in sensory gating paradigms.10, 18


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)

Cartoon schematic of the hypothesized neuronal circuit responsible for sensory gating and its deficits in schizophrenia. Waveform positive polarity is upwards. (a) In a healthy subject, a sound stimulus excites Neuron 1 (for example, the perforant path (PP) input to the hippocampus), which in turn excites hippocampal pyramidal Neuron 3. Neuron 1 also excites inhibitory Neuron 2. (b) Neuron 2 reduces glutamate release by Neuron 1 via activation of presynaptic GABA-B receptors (slow inhibition) as well as inhibits Neuron 3 via activation of postsynaptic GABA-A receptors (fast inhibition). (c) Step 3: a second sound stimulus arrives 500 ms later and excites Neuron 1. Unlike the previous stimulus, Neuron 1 cannot excite Neuron 3 owing to persistent (slow) inhibition from Neuron 2. Signal from the second stimulus is, therefore, reduced or ‘gated.' (d) In a patient with schizophrenia, gating deficits may arise from reduced GABAergic signaling caused by dysfunction of Neuron 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Cartoon schematic of the hypothesized neuronal circuit responsible for sensory gating and its deficits in schizophrenia. Waveform positive polarity is upwards. (a) In a healthy subject, a sound stimulus excites Neuron 1 (for example, the perforant path (PP) input to the hippocampus), which in turn excites hippocampal pyramidal Neuron 3. Neuron 1 also excites inhibitory Neuron 2. (b) Neuron 2 reduces glutamate release by Neuron 1 via activation of presynaptic GABA-B receptors (slow inhibition) as well as inhibits Neuron 3 via activation of postsynaptic GABA-A receptors (fast inhibition). (c) Step 3: a second sound stimulus arrives 500 ms later and excites Neuron 1. Unlike the previous stimulus, Neuron 1 cannot excite Neuron 3 owing to persistent (slow) inhibition from Neuron 2. Signal from the second stimulus is, therefore, reduced or ‘gated.' (d) In a patient with schizophrenia, gating deficits may arise from reduced GABAergic signaling caused by dysfunction of Neuron 2.
Mentions: A remarkable aspect of P50 gating is the simplicity behind the neuronal circuitry that may underlie the phenomenon.16 In its most basic form, this process can be accomplished with only three neurons: two excitatory neurons and an intermediate inhibitory neuron (Figure 2). In the paired-click paradigm, the first, ‘conditioning' stimulus (S1) excites Neuron 1, which in turn excites inhibitory Neuron 2 and excitatory pyramidal Neuron 3 (Figure 2a). Activation of Neuron 2, in turn, induces release of the inhibitory neurotransmitter GABA. GABA release causes fast inhibition of Neuron 3 via postsynaptic GABA-A receptors as well as slow, persistent inhibition of glutamate release onto Neuron 3 from Neuron 1 (via presynaptic GABA-B receptors17). Persistent inhibition in particular diminishes the response of Neuron 3 for up to 8 s (Figure 2b).9 Consequently, if the second, ‘test' stimulus (S2) arrives <1 s after S1, S2 event-related potential amplitude is reduced compared with S1 (Figure 2c). A reduction of the ability of Neuron 2 to modulate this circuit (for example, by reduced α7 nicotinic receptor expression on inhibitory Neuron 2) is postulated to underlie gating deficits in schizophrenia (Figure 2d).16 These deficits are maximal when stimuli are spaced 0.5 s apart, as typically presented in sensory gating paradigms.10, 18

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