ReviewViagra for your synapses: Enhancement of hippocampal long-term potentiation by activation of beta-adrenergic receptors
Introduction
A major goal of neuroscience research is to determine how enduring memories are made. Such knowledge would enhance therapies for memory disorders and illuminate many key brain functions that rely on enduring memories. Activity-induced changes in synaptic strength (“synaptic plasticity”) are widely believed to underlie memory storage at the cellular level [1], [2]. Research has established the principle that synaptic plasticity is critical for associative learning and long-term memory [3], [4]. In the mammalian hippocampus, a brain structure critical for making new memories, one form of synaptic plasticity, called “long-term potentiation” (LTP) [5], has been linked to spatial and contextual learning and memory [1], [6]. LTP is an activity-dependent increase in excitatory synaptic strength that can last for several hours in isolated brain slice preparations and up to a year in intact animals [7], [8]. Many key signaling requirements for LTP (e.g. NMDA receptors, protein kinase-A, calcium-dependent protein kinases) mirror those needed for memory storage in the mammalian brain [6], [9], [10], [11], [12], [13], [14], [15]. Many manipulations that modify LTP also alter memory expression. Importantly, LTP-like changes in synaptic efficacy can occur in behaving animals as they learn [4]. Since its discovery by Tim Bliss and Terje Lomo [5], LTP has become the leading candidate synaptic mechanism for memory storage in the mammalian brain.
Many neuromodulatory transmitters control the endurance of LTP and memory. One neuromodulator that can significantly enhance hippocampal LTP stability is noradrenaline (NA). NA fibers originate mainly in the locus coeruleus (LC) [16]. LC projects widely throughout the forebrain, providing dense innervation to the hippocampus, amygdala, and thalamus [16]. As such, NA can influence many key brain functions such as attention, arousal, sleep, learning, and memory. The hippocampus is richly innervated by noradrenergic fibers from the LC, and endogenous release of NA can induce persistent synaptic plasticity [17], [18]. Interestingly, hippocampus-dependent memory is impaired following reduction of NA or after blockade of β-ARs [19], [20]. In the hippocampus, NA binds to β-ARs to enhance the endurance of LTP and promote stability of memories. However, the signaling mechanisms that enable β-ARs to enhance the longevity of LTP are unclear. Because LTP has been strongly correlated with memory storage, understanding how β-ARs modulate the persistence of LTP will shed light on how these receptors regulate memory storage. In this review, we highlight several signaling mechanisms believed to enable β-ARs to enhance the expression of long-lasting forms of hippocampal LTP. We focus on hippocampal β-ARs because of the important roles of these receptors in enhancing LTP and memory. α-ARs are not covered here; their roles in hippocampal synaptic plasticity and memory storage are reviewed elsewhere [21].
Section snippets
β-AR signaling: importance for synaptic plasticity in the mammalian hippocampus
NA binds to noradrenergic receptors coupled to G-proteins that initiate intracellular signaling. These can be broadly classified as α1-, α2-, β1-, and β2-ARs [21]. In the hippocampus, all four of these receptor subtypes are expressed in pyramidal neurons and dentate granule cells [22], [23]. β-ARs are also expressed outside of the hippocampus, mainly in the cortex, thalamus, and cerebellum [22], [24]. Interneurons apparently express very few or no β-ARs [22], [23], and glia in area CA1 express
Regulatory control of β-AR signaling
Intracellular signaling events engaged by β-AR activation have several regulatory feedback mechanisms that serve to both prevent activation of downstream effectors in the absence of β-AR agonists and amplify β-AR-dependent responses by compartmentalizing second messenger signaling [36]. Phosphodiesterases (PDEs) are the primary enzymes for cAMP degradation and can constrain β-AR-dependent cellular responses. The primary PDE isoform in the CNS is PDE4 and regulation of β-AR desensitization is
Modulation of excitability by hippocampal β-ARs
Neuromodulators can affect neuronal ability to undergo synaptic plasticity by changing cellular excitability. Activation of β-ARs generally increases the excitability of principal neurons in the dentate gyrus, area CA3, and area CA1 of the rodent hippocampus. In the dentate gyrus, application of either NA or a β-adrenergic agonist such as isoproterenol induces pathway-specific changes in cellular excitability. β-AR-mediated enhancement of the population spike is observed in the medial perforant
β-AR modulation of hippocampal LTP
Highly significant events are easily remembered, often for an entire lifetime. There is evidence to suggest that the physiologic mechanism underlying this retention is related to activation of the brain's noradrenergic system, which promotes plasticity in brain structures that mediate enduring behavioral adaptations [61], [62]. A plausible cellular mechanism for enhancement of hippocampal memory by β-ARs is facilitation of enduring LTP by β-ARs. This phenomenon can be studied in vitro by
PKA-independent β-AR signaling
Traditionally, cAMP-dependent signaling in hippocampal neurons has been thought to be mediated primarily through PKA (for review, see [29]). However, novel cAMP receptors (Epac 1 and 2) also participate in neuronal cAMP-dependent signaling. Epac-dependent, PKA-independent modulation of cellular processes has been demonstrated at the crayfish neuromuscular junction [129], the calyx of Held [130], and in cortical neurons [131]. In the hippocampus, Epac contributes to the forskolin response in
Roles of translational regulation in β-AR modulation of LTP
The inhibitory effects of translation inhibitors on LTP can be detected as early as 20 min after induction [137], [138], [139]. Thus, plasticity-related proteins can be produced rapidly and locally in dendrites after electrical stimulation. Indeed, dendritic expression of some proteins is increased within 5 min after LTP induction [138]. LTP induced by pairing isoproterenol with one 100-Hz train of HFS (“β-LTP”) requires dendritic translation, but not transcription [84]. Other forms of
Prospects for future research: signaling complexes and glutamate receptors
An important principle in intracellular signaling is the key role played by adaptor or scaffolding proteins that couple protein kinases and other signaling molecules near their upstream activators and downstream targets, thereby forming signaling complexes that enable fast, efficient, and highly localized signaling. A prominent family of scaffolding proteins that serves this function for the cAMP/PKA signaling pathway is the A-kinase anchoring proteins (AKAPs), a family of more than 50 proteins
Acknowledgements
T.J.O. was supported by National Institute of Mental Health grant MH609197. S.A.C. was supported by a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council of Canada. P.V.N. is a Scientist of the Alberta Heritage Foundation for Medical Research, and received research support from the Canadian Institutes of Health Research.
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