The Journal of Neuroscience, 1999, 19:RC23:1-5
RAPID COMMUNICATION
Activation of cAMP-Dependent Protein Kinase A in Prefrontal
Cortex Impairs Working Memory Performance
Jane R.
Taylor1,
Shari
Birnbaum2,
Ravi
Ubriani2, and
Amy F. T.
Arnsten2
1 Department of Psychiatry and 2 Section of
Neurobiology, Yale University School of Medicine, New Haven,
Connecticut 06520-8001
Activation of the adenylyl cyclase-cAMP-protein kinase A (PKA)
intracellular signaling cascade is necessary for long-term memory
consolidation in brain regions such as the hippocampus. However, the
role of the PKA cascade in the working memory functions of the
prefrontal cortex (PFC) is unknown. The present study examined the
effects of manipulating PKA activity in the PFC using the cAMP
stereoisomers Sp-cAMPS and Rp-cAMPS, which activate and inhibit PKA,
respectively. Animals received bilateral infusions of Sp-cAMPS and/or
Rp-cAMPS into the PFC immediately before testing on the delayed
alternation task, a test of spatial working memory that depends on the
integrity of the PFC. Low doses of Sp-cAMPS (0.21, 2.1, or 21 nmol/0.5
µl) produced a marked, dose-dependent impairment in working memory
performance. The impairment produced by infusion of Sp-cAMPS (21 nmol/0.5 µl) was fully reversed by co-infusion of Rp-cAMPS (21 nmol/0.5 µl), consistent with actions on PKA. Rp-cAMPS (21 or 42 nmol/0.5 µl) by itself had no effect on performance. These results
indicate that activation of the PKA intracellular signaling cascade in
the PFC impairs working memory performance. The current findings
contrast with studies of long-term memory consolidation, in which
inhibition of PKA with agents such as Rp-cAMPS impaired memory
consolidation (Bernabeu et al., 1997; Bourtchouladze et al., 1998),
whereas enhancement of the PKA pathway improved memory (Bernabeu et
al., 1997; Barad et al., 1998). These results demonstrate that discrete
cognitive processes subserved by different cortical regions are
mediated by distinct intracellular mechanisms.
Key words:
Sp-cAMPS; Rp-cAMPS; delayed alternation; rats; intracellular signals; PKA; memory
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