Dysregulation of protein kinase A signaling in the aged prefrontal cortex: New strategy for treating age-related cognitive decline

Brian P. Ramos; Shari G. Birnbaum; Isabelle Lindenmayer; Samuel S. Newton; Ronald S. Duman; Amy F.T. Arnsten

doi:10.1016/S0896-6273(03)00694-9

Dysregulation of protein kinase A signaling in the aged prefrontal cortex: New strategy for treating age-related cognitive decline

Brian P. Ramos, Shari G. Birnbaum, Isabelle Lindenmayer, Samuel S. Newton, Ronald S. Duman, Amy F.T. Arnsten

Research output: Contribution to journal › Article › peer-review

203 Scopus citations

Abstract

Activation of the cAMP/protein kinase A (PKA) pathway has been proposed as a mechanism for improving age-related cognitive deficits based on studies of hippocampal function. However, normal aging also afflicts prefrontal cortical cognitive functioning. Here, we report that agents that increase PKA activity impair rather than improve prefrontal cortical function in aged rats and monkeys with prefrontal cortical deficits. Conversely, PKA inhibition ameliorates prefrontal cortical cognitive deficits. Western blot and immunohistochemical analyses of rat brain further indicate that the cAMP/PKA pathway becomes disinhibited in the prefrontal cortex with advancing age. These data demonstrate that PKA inhibition, rather than activation, is the appropriate strategy for restoring prefrontal cortical cognitive abilities in the elderly.

Original language	English (US)
Pages (from-to)	835-845
Number of pages	11
Journal	Neuron
Volume	40
Issue number	4
DOIs	https://doi.org/10.1016/S0896-6273(03)00694-9
State	Published - Nov 13 2003
Externally published	Yes

ASJC Scopus subject areas

Neuroscience(all)

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10.1016/S0896-6273(03)00694-9

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title = "Dysregulation of protein kinase A signaling in the aged prefrontal cortex: New strategy for treating age-related cognitive decline",

abstract = "Activation of the cAMP/protein kinase A (PKA) pathway has been proposed as a mechanism for improving age-related cognitive deficits based on studies of hippocampal function. However, normal aging also afflicts prefrontal cortical cognitive functioning. Here, we report that agents that increase PKA activity impair rather than improve prefrontal cortical function in aged rats and monkeys with prefrontal cortical deficits. Conversely, PKA inhibition ameliorates prefrontal cortical cognitive deficits. Western blot and immunohistochemical analyses of rat brain further indicate that the cAMP/PKA pathway becomes disinhibited in the prefrontal cortex with advancing age. These data demonstrate that PKA inhibition, rather than activation, is the appropriate strategy for restoring prefrontal cortical cognitive abilities in the elderly.",

author = "Ramos, {Brian P.} and Birnbaum, {Shari G.} and Isabelle Lindenmayer and Newton, {Samuel S.} and Duman, {Ronald S.} and Arnsten, {Amy F.T.}",

note = "Funding Information: The authors would like to thank Tracy Sadlon, Lisa Ciavarella, Sam Johnson, and Rose Terwilliger for their invaluable technical assistance. This research was supported by NIH grants MH45481 to R.S.D. and MERIT Award AG06036 to A.F.T.A.",

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AU - Newton, Samuel S.

AU - Duman, Ronald S.

AU - Arnsten, Amy F.T.

N1 - Funding Information: The authors would like to thank Tracy Sadlon, Lisa Ciavarella, Sam Johnson, and Rose Terwilliger for their invaluable technical assistance. This research was supported by NIH grants MH45481 to R.S.D. and MERIT Award AG06036 to A.F.T.A.

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N2 - Activation of the cAMP/protein kinase A (PKA) pathway has been proposed as a mechanism for improving age-related cognitive deficits based on studies of hippocampal function. However, normal aging also afflicts prefrontal cortical cognitive functioning. Here, we report that agents that increase PKA activity impair rather than improve prefrontal cortical function in aged rats and monkeys with prefrontal cortical deficits. Conversely, PKA inhibition ameliorates prefrontal cortical cognitive deficits. Western blot and immunohistochemical analyses of rat brain further indicate that the cAMP/PKA pathway becomes disinhibited in the prefrontal cortex with advancing age. These data demonstrate that PKA inhibition, rather than activation, is the appropriate strategy for restoring prefrontal cortical cognitive abilities in the elderly.

AB - Activation of the cAMP/protein kinase A (PKA) pathway has been proposed as a mechanism for improving age-related cognitive deficits based on studies of hippocampal function. However, normal aging also afflicts prefrontal cortical cognitive functioning. Here, we report that agents that increase PKA activity impair rather than improve prefrontal cortical function in aged rats and monkeys with prefrontal cortical deficits. Conversely, PKA inhibition ameliorates prefrontal cortical cognitive deficits. Western blot and immunohistochemical analyses of rat brain further indicate that the cAMP/PKA pathway becomes disinhibited in the prefrontal cortex with advancing age. These data demonstrate that PKA inhibition, rather than activation, is the appropriate strategy for restoring prefrontal cortical cognitive abilities in the elderly.

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Dysregulation of protein kinase A signaling in the aged prefrontal cortex: New strategy for treating age-related cognitive decline

Abstract

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