Activation of β2-adrenoceptor enhances synaptic potentiation and behavioral memory via cAMP-PKA signaling in the medial prefrontal cortex of rats.

The prefrontal cortex (PFC) plays a critical role in cognitive functions, including working memory, attention regulation, behavioral inhibition, as well as memory storage. The functions of PFC are very sensitive to norepinephrine (NE), and even low levels of endogenously released NE exert a dramatic influence on the functioning of the PFC. Activation of β-adrenoceptors (β-ARs) facilitates synaptic potentiation and enhances memory in the hippocampus. However, little is known regarding these processes in the PFC. In the present study, we investigate the role of β2-AR in synaptic plasticity and behavioral memory. Our results show that β2-AR selective agonist clenbuterol facilitates spike-timing-dependent long-term potentiation (tLTP) under the physiological conditions with intact GABAergic inhibition, and such facilitation is prevented by co-application with the cAMP inhibitor Rp-cAMPS. Loading postsynaptic pyramidal cells with Rp-cAMPS, the PKA inhibitor PKI(5-24), or the G protein inhibitor GDP-β-S significantly decreases, but does not eliminate, the effect of clenbuterol. Clenbuterol suppresses the GABAergic transmission, while blocking GABAergic transmission by the GABA(A) receptor blocker partially mimics the effect of clenbuterol. In behavioral tests, a post-training infusion of clenbuterol into mPFC enhances 24-h trace fear memory. In summary, we observed that prefrontal cortical β2-AR activation by clenbuterol facilitates tLTP and enhances trace fear memory. The mechanism underlying tLTP facilitation involves stimulating postsynaptic cAMP-PKA signaling cascades and suppressing GABAergic circuit activities.

[1]  Tommaso Patriarchi,et al.  β2-Adrenergic receptor supports prolonged theta tetanus-induced LTP. , 2012, Journal of neurophysiology.

[2]  M. Zhuo,et al.  Rapid synaptic potentiation within the anterior cingulate cortex mediates trace fear learning , 2012, Molecular Brain.

[3]  M. Atzori,et al.  Pre‐ and postsynaptic effects of norepinephrine on γ‐aminobutyric acid‐mediated synaptic transmission in layer 2/3 of the rat auditory cortex , 2012, Synapse.

[4]  Elke Edelmann,et al.  Dopamine Modulates Spike Timing-Dependent Plasticity and Action Potential Properties in CA1 Pyramidal Neurons of Acute Rat Hippocampal Slices , 2011, Front. Syn. Neurosci..

[5]  Christina B. Castelino,et al.  Stress and Glucocorticoids Impair Memory Retrieval via β2-Adrenergic, Gi/o-Coupled Suppression of cAMP Signaling , 2011, The Journal of Neuroscience.

[6]  Steven A. Connor,et al.  Activation of β‐adrenergic receptors facilitates heterosynaptic translation‐dependent long‐term potentiation , 2011, The Journal of physiology.

[7]  S. Thomas,et al.  Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled β2-adrenergic signaling. , 2011, Learning & memory.

[8]  M. Miranda,et al.  β-Adrenergic receptors in the insular cortex are differentially involved in aversive vs. incidental context memory formation. , 2011, Learning & memory.

[9]  W. Yao,et al.  D1 and D2 dopamine receptors in separate circuits cooperate to drive associative long-term potentiation in the prefrontal cortex , 2010, Proceedings of the National Academy of Sciences.

[10]  A. Marzo,et al.  Cellular mechanisms of long-term depression induced by noradrenaline in rat prefrontal neurons , 2010, Neuroscience.

[11]  F. Helmstetter,et al.  Trace and contextual fear conditioning require neural activity and NMDA receptor-dependent transmission in the medial prefrontal cortex. , 2010, Learning & memory.

[12]  V. Bolshakov,et al.  Emotional enhancement of memory: how norepinephrine enables synaptic plasticity , 2010, Molecular Brain.

[13]  Steven A. Connor,et al.  Viagra for your synapses: Enhancement of hippocampal long-term potentiation by activation of beta-adrenergic receptors. , 2010, Cellular signalling.

[14]  N. Koshikawa,et al.  Presynaptic interneuron subtype- and age-dependent modulation of GABAergic synaptic transmission by beta-adrenoceptors in rat insular cortex. , 2010, Journal of neurophysiology.

[15]  G. Bi,et al.  Gain in sensitivity and loss in temporal contrast of STDP by dopaminergic modulation at hippocampal synapses , 2009, Proceedings of the National Academy of Sciences.

[16]  N. Lemon,et al.  Locus Coeruleus Activation Facilitates Memory Encoding and Induces Hippocampal LTD that Depends on β-Adrenergic Receptor Activation , 2009, Cerebral cortex.

[17]  N. Koshikawa,et al.  Presynaptic and postsynaptic modulation of glutamatergic synaptic transmission by activation of α1‐ and β‐adrenoceptors in layer V pyramidal neurons of rat cerebral cortex , 2009, Synapse.

[18]  S. Sara.  The locus coeruleus and noradrenergic modulation of cognition , 2009, Nature Reviews Neuroscience.

[19]  A. Arnsten,et al.  β2 adrenergic agonist, clenbuterol, enhances working memory performance in aging animals , 2008, Neurobiology of Aging.

[20]  Ze-Jun Feng,et al.  Pre- and postsynaptic beta-adrenergic activation enhances excitatory synaptic transmission in layer V/VI pyramidal neurons of the medial prefrontal cortex of rats. , 2008, Cerebral cortex.

[21]  M. Zhuo,et al.  Genetic enhancement of trace fear memory and cingulate potentiation in mice overexpressing Ca2+/calmodulin‐dependent protein kinase IV , 2008, The European journal of neuroscience.

[22]  Emilie Campanac,et al.  Spike timing‐dependent plasticity: a learning rule for dendritic integration in rat CA1 pyramidal neurons , 2008, The Journal of physiology.

[23]  Marco Fuenzalida,et al.  Changes of the EPSP Waveform Regulate the Temporal Window for Spike-Timing-Dependent Plasticity , 2007, The Journal of Neuroscience.

[24]  A. Kirkwood,et al.  Neuromodulators Control the Polarity of Spike-Timing-Dependent Synaptic Plasticity , 2007, Neuron.

[25]  D. McCormick,et al.  α2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting cAMP-HCN Channel Signaling in Prefrontal Cortex , 2007, Cell.

[26]  Huibert D. Mansvelder,et al.  Distributed Network Actions by Nicotine Increase the Threshold for Spike-Timing-Dependent Plasticity in Prefrontal Cortex , 2007, Neuron.

[27]  F. Mascagni,et al.  Pyramidal cells of the rat basolateral amygdala: Synaptology and innervation by parvalbumin‐immunoreactive interneurons , 2006, The Journal of comparative neurology.

[28]  M. McEchron,et al.  Single neurons in the medial prefrontal cortex of the rat exhibit tonic and phasic coding during trace fear conditioning. , 2005, Behavioral neuroscience.

[29]  Peter V. Nguyen,et al.  β-Adrenergic Receptor Activation Facilitates Induction of a Protein Synthesis-Dependent Late Phase of Long-Term Potentiation , 2005, The Journal of Neuroscience.

[30]  Y. Dan,et al.  Spike-timing-dependent synaptic plasticity depends on dendritic location , 2005, Nature.

[31]  S. Tronel,et al.  Noradrenergic action in prefrontal cortex in the late stage of memory consolidation. , 2004, Learning & memory.

[32]  P. Dash,et al.  A Role for Prefrontal Cortex in Memory Storage for Trace Fear Conditioning , 2004, The Journal of Neuroscience.

[33]  O. Paulsen,et al.  Maturation of Long-Term Potentiation Induction Rules in Rodent Hippocampus: Role of GABAergic Inhibition , 2003, The Journal of Neuroscience.

[34]  Thomas Straube,et al.  Requirement of β‐adrenergic receptor activation and protein synthesis for LTP‐reinforcement by novelty in rat dentate gyrus , 2003 .

[35]  Christof Koch,et al.  Trace but not delay fear conditioning requires attention and the anterior cingulate cortex , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. Min,et al.  Enhancement of Associative Long-Term Potentiation by Activation of β-Adrenergic Receptors at CA1 Synapses in Rat Hippocampal Slices , 2003, The Journal of Neuroscience.

[37]  Bao-Ming Li,et al.  Deficit in long‐term contextual fear memory induced by blockade of β‐adrenoceptors in hippocampal CA1 region , 2003, The European journal of neuroscience.

[38]  C. Berridge,et al.  The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes , 2003, Brain Research Reviews.

[39]  Brian K. Kobilka,et al.  Mutation of the α2A-Adrenoceptor Impairs Working Memory Performance and Annuls Cognitive Enhancement by Guanfacine , 2002, The Journal of Neuroscience.

[40]  E. Baldi,et al.  Differential contribution of some cortical sites to the formation of memory traces supporting fear conditioning , 2002, Experimental Brain Research.

[41]  P. J. Sjöström,et al.  Spike timing, calcium signals and synaptic plasticity , 2002, Current Opinion in Neurobiology.

[42]  Eric R. Kandel,et al.  Fear Conditioning Occludes LTP-Induced Presynaptic Enhancement of Synaptic Transmission in the Cortical Pathway to the Lateral Amygdala , 2002, Neuron.

[43]  E. Kandel.  The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses , 2001, Science.

[44]  B. Kobilka,et al.  β-Adrenergic Receptor Subtype-Specific Signaling in Cardiac Myocytes from β1 and β2 Adrenoceptor Knockout Mice , 2001 .

[45]  S. Sesack,et al.  Ultrastructural localization of the serotonin transporter in superficial and deep layers of the rat prelimbic prefrontal cortex and its spatial relationship to dopamine terminals , 2000 .

[46]  S. Satake,et al.  beta-adrenergic receptor-mediated presynaptic facilitation of inhibitory GABAergic transmission at cerebellar interneuron-Purkinje cell synapses. , 2000, Journal of neurophysiology.

[47]  James K. Kroger,et al.  Cross-modal and cross-temporal association in neurons of frontal cortex , 2000, Nature.

[48]  M. Wilson,et al.  Formation of Temporal Memory Requires NMDA Receptors within CA1 Pyramidal Neurons , 2000, Neuron.

[49]  Bao-Ming Li,et al.  Alpha-2 Adrenergic Modulation of Prefrontal Cortical Neuronal Activity Related to Spatial Working Memory in Monkeys , 1999, Neuropsychopharmacology.

[50]  Bao-Ming Li,et al.  Local infusion of an α-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys , 1999, Biological Psychiatry.

[51]  JaneR . Taylor,et al.  A role for norepinephrine in stress-induced cognitive deficits: α-1-adrenoceptor mediation in the prefrontal cortex , 1999, Biological Psychiatry.

[52]  James L. McGaugh,et al.  Basolateral Amygdala Noradrenergic Influences on Memory Storage Are Mediated by an Interaction between β- and α1-Adrenoceptors , 1999, The Journal of Neuroscience.

[53]  A. Arnsten,et al.  The α-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys , 1998, Psychopharmacology.

[54]  T. Robbins,et al.  Dissociable Forms of Inhibitory Control within Prefrontal Cortex with an Analog of the Wisconsin Card Sort Test: Restriction to Novel Situations and Independence from “On-Line” Processing , 1997, The Journal of Neuroscience.

[55]  Robert J. Lefkowitz,et al.  Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A , 1997, Nature.

[56]  J. Jentsch,et al.  The Alpha-1 Adrenergic Agonist, Cirazoline, Impairs Spatial Working Memory Performance in Aged Monkeys , 1997, Pharmacology Biochemistry and Behavior.

[57]  E. Fuchs,et al.  β-Adrenoceptors in the Tree Shrew Brain. I. Distribution and Characterization of [125I]Iodocyanopindolol Binding Sites , 1997, Cellular and Molecular Neurobiology.

[58]  Y. Izumi,et al.  Noradrenergic regulation of synaptic plasticity in the hippocampal CA1 region. , 1997, Journal of neurophysiology.

[59]  H. Markram,et al.  Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs , 1997, Science.

[60]  D. Johnston,et al.  A Synaptically Controlled, Associative Signal for Hebbian Plasticity in Hippocampal Neurons , 1997, Science.

[61]  H. Yeh,et al.  Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: cyclic AMP as intracellular intermediary , 1996, Neuroscience.

[62]  T. Jay,et al.  NMDA Receptor‐dependent Long‐term Potentiation in the Hippocampal Afferent Fibre System to the Prefrontal Cortex in the Rat , 1995, The European journal of neuroscience.

[63]  E. Lakatta,et al.  Functional coupling of the beta 2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. , 1995, Molecular pharmacology.

[64]  T. Bliss,et al.  A synaptic model of memory: long-term potentiation in the hippocampus , 1993, Nature.

[65]  Serge Laroche,et al.  Long-term potentiation in the prefrontal cortex following stimulation of the hippocampal CA1/subicular region , 1990, Neuroscience Letters.

[66]  M. Tabaton,et al.  Adrenergic Receptors in Aging and Alzheimer's Disease: Increased β2‐Receptors in Prefrontal Cortex and Hippocampus , 1989, Journal of neurochemistry.

[67]  B. Waterhouse,et al.  Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: evidence for mediation through the β-adrenoceptor-coupled cyclic AMP system , 1989, Brain Research.

[68]  J. Morrison,et al.  Noradrenergic innervation of monkey prefrontal cortex: A dopamine‐β‐hydroxylase immunohistochemical study , 1989, The Journal of comparative neurology.

[69]  P. Goldman-Rakic,et al.  The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[70]  J. O'Donnell,et al.  Effects of clenbuterol on central beta-1 and beta-2 adrenergic receptors of the rat. , 1987, The Journal of pharmacology and experimental therapeutics.

[71]  P. Goldman-Rakic,et al.  Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. , 1985, Science.

[72]  R. Anwyl,et al.  Inhibition of the slow afterhyperpolarization restores the classical spike timing-dependent plasticity rule obeyed in layer 2/3 pyramidal cells of the prefrontal cortex. , 2012, Journal of neurophysiology.

[73]  P. Goldman-Rakic.  Circuitry of Primate Prefrontal Cortex and Regulation of Behavior by Representational Memory , 2011 .

[74]  J. Mcgaugh,et al.  Involvement of the amygdala in the memory-enhancing effects of clenbuterol , 2005, Psychopharmacology.

[75]  J. Fuster.  Cortex and mind : unifying cognition , 2003 .

[76]  G. Bi,et al.  Synaptic modification by correlated activity: Hebb's postulate revisited. , 2001, Annual review of neuroscience.

[77]  E. Miller,et al.  An integrative theory of prefrontal cortex function. , 2001, Annual review of neuroscience.

[78]  M. Segal,et al.  Plasticity of sensory responses of locus coeruleus neurons in the behaving rat: implications for cognition. , 1991, Progress in brain research.

[79]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .