Sleep is a critical anabolic state that plays a crucial role in memory consolidation. As such, many theories overlap in indicating that sleep deprivation (SD) affects the neuronal functioning in the hippocampus (McDermott et al, 2003). In particular, synaptic plasticity and neuronal excitability in this region of the brain are found to be vulnerable when SD is induced (McDermott et al, 2003). Given the societal prevalence of SD and its associated cognitive impairments, it is critical to be able to distinguish its cellular and molecular basis. The primary theory which will be elucidated in the subsequent paragraphs will concern the role of cyclic adenosine 3', 5'-monophosphate (cAMP) and cAMP-dependant protein kinase A (PKA) in hippocampal synaptic plasticity under normal and SD conditions. The potential for novel therapies to reduce the effects of SD will also be briefly highlighted based on the postulates presented.
Synaptic plasticity is conventionally defined as the neuronal capacity to change the strength of intercellular communication (McDermott et al, 2003). The synaptic plasticity of neurons is influenced by the level of interaction with available neurotransmitters and other neurochemicals which modulate such reactions (McDermott et al, 2003). Most critically, it has been repeatedly shown that memories are retained in the mammalian brain due to extensive networks of synaptic activity most densely located in the hippocampal region (Guan et al, 2004). These networks are most commonly reactivated and consolidated during post-learning sleep to form memories (Guan et al, 2004). Under normal conditions in which an individual has attained the required amount of sleep in accordance to their age and physical conditioning, the consolidation of memory and expression of learning is a simple process. Synaptic plasticity is attained through reversible protein phosphorylation regulated by protein kinase A (PKA) (Nguyen & Woo, 2003). Linked to this kinase is the intracellular messenger cAMP, which directly activates cAMP-dependant PKA (Nguyen & Woo, 2003).
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When the cAMP/PKA signalling process commences, there are only two established mechanisms to consider based on the collective information presented in Nguyen & Woo, 2003. In the first proposed mechanism, calmodulin-sensitive adenylyl cyclase (cAMP precursor) is stimulated by calcium. This is done through a process described by Eliot et al., 1989 in which N-methyl-D-aspartic acid (NMDA) receptors are used for ion movement (Nguyen & Woo, 2003). As a result, there is a subsequent increase in the levels of cAMP found in the CA1 region of the hippocampus (Nguyen & Woo, 2003). The second, more widely accepted cAMP initiatory model involves neurotransmitters such as glutamate, and dopamine as indicated by Tang and Gilman, 1991 (Nguyen & Woo, 2003). When these neurotransmitters bind to their respective receptors, a similar mechanism to the one described above is seen as adenylyl cyclase is activated. However, in this case, guanine nucleotide-binding regulatory proteins, or "G-proteins" as described by Nguyen & Woo, 2003 may also activate adenylyl cyclase. Both of these proposed mechanisms for cAMP activation finish in cAMP being subsequently produced and bound to subunits on inactivated PKA holoenzymes (Nguyen & Woo, 2003). Once this occurs, one of three monomeric catalytic (C) subunits located on the PKA enzyme will be dissociated from the complex as highlighted by Taylor et al, 1990 in Nguyen & Woo, 2003. What follows is simply the phosphorylation of serine and threonine residues on surrounding proteins conducted by the separated C subunits (Nguyen & Woo, 2003). On a molecular basis of this phosphorylation, there will be a transfer of terminal phosphates from ATP onto the serine and threonine residues of surrounding proteins, thereby increasing the activity (i.e. Synaptic plasticity) in the region.
What is more interesting is that "A kinase anchoring proteins" (AKAPS) compete with cAMP for binding sites on PKA (Nguyen & Woo, 2003). Intuitively, what would be thought is that this would reduce the levels of signal transduction. However, the spatial confinement permits a relative "selective regulation of effector proteins at higher levels of enzymatic efficiency" as stated by Nguyen & Woo, 2003. When exchanging lenses for a broader look at the tissue level, this efficient system may indicate how the cAMP/PKA signalling system is able to be a multi-regulatory process which affects the neuronal excitability, ion channel conductance, and neuronal cell motility in the hippocampus. This would further the notion that SD would affect a multitude of neuronal activities.
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Now when examining the intrinsic cellular basis of sleep deprivation, a much more depleted system is seen. As stated above, a large consequence of sleep deprivation is impaired functioning in memory consolidation and learning. This was found to be attributable to a combination of impaired hippocampal functioning through reduced cAMP/PKA signalling, and increased levels of cAMP-inhibitory enzymes (Vecsey et al., 2009). In Vecsey et al., 2009, it was highlighted that SD reduces the levels of cAMP in CA1 hippocampal regions. The researchers were able to demonstrate that SD decreases the ability for neurons in the CA1 region to react with calmodulin-sensitive adenylyl cyclases, thereby resulting in reduced levels of cAMP Vecsey et al., 2009. This also causes for a subsequent reduction in the number cAMP bound to PKA, and the number of C subunits able to detach and phosphorylate surrounding proteins. The largest contributor to the impairment of cAMP/PKA signalling is the presence of cyclic nucleotide phosphodiesterases (PDEs) as highlighted by Houslay et al, 2003 in Vecsey et al., 2009. These are degradative cAMP-inhibitory enzymes which are found in increased levels during SD. In particular, PDE4A5-specific cAMP strains are found in CA1 hippocampal regions that convert cAMP to AMP (Vecsey et al., 2009). An interesting finding by Houslay et al., 2005, has found that during SD, the presence of PDE4 sets thresholds for cAMP/PKA induction which make it harder for subsequent phosphorylation of proteins (Vecsey et al., 2009). Now when relocating the scope of the analysis in a "top-down" fashion, the lack of phosphorylation causes for less activation of proteins. Less activation of proteins results in a decreased neuronal activity. A decrease in neuronal activity results in decreased ability for intercellular communication, and therefore, impaired functioning in the presence of neurotransmitters. Ultimately, a resultant decrease in synaptic plasticity will be seen.
Apart from the strict advice for more sleep, when examining SD treatment approaches, it is imperative to develop novel therapies which target the cAMP/PKA processes. In particular inhibitory agents which aim to reduce cAMP deficit caused by PDE enzymes would be the most probable treatment approach.
In conclusion, sleep deprivation greatly impairs the multi-regulatory processes associated with cAMP/PKA signalling. This subsequently causes for decreased synaptic plasticity and membrane excitability in the hippocampus. The location of such impaired processes results in compromised memory consolidation and retentive learning processes. As such, it is imperative to avoid sleep deprivation as sleep is a crucial anabolic state that affects a multitude of neuronal activities.
Word Count w/o in text references & reference list: 931
Word Count w/in text references & reference list: 1021