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shows some examples of synaptic plasticity across a large temporal spectrum. In vivo optical imaging of postsynaptic compartments in glutamatergic neurons, so-called ► dendritic spines, suggests that synaptic plasticity is the rule rather than the exception in the lifetime of a synapse.

Impact of Psychoactive Drugs

The diversity of synaptic plasticity implicates that there are numerous potential pharmacological mechanisms that affect synapses and their function. The below-given examples only reflect a selection of the better studied links between psychopharmaceuticals and synaptic plasticity. As for many other aspects of psychoactive drugs, we have to acknowledge that there are still many gaps in our understanding of their molecular mechanism of action and link to synaptic function. As a general rule - taking into consideration the prerequisite for ► spatio-temporal coincidence - it is helpful for deciphering such links to focus on ► second messenger systems triggered by targets of psychopharmacological drugs and study their effect on synaptic proteins that are involved in the above-described plasticity process.

Linking Dopamine Receptors with NMDA Receptors via DARPP-32

A prominent example of this approach is the link between ► dopamine and N-methyl-D-aspartate ► (NMDA) receptors that are key mediators of many forms of LTP. This connection may even provide a molecular basis for the clinical manifestation of both positive and negative symptoms in schizophrenia via the mutual interaction between dopaminergic and glutamatergic signaling networks (Stone et al. 2007). Phosphorylation of the dopamine and cAMPregulated phosphoprotein (► DARPP-32) by either dopamine receptor-induced protein kinase A (PKA) or by NMDA receptor-triggered calcineurin reciprocally affects either receptor system via protein phosphatase 1 (PP1), and modulates the late phase of LTP by influencing the extracellular signal-regulated kinase (ERK) pathway. With its multiple phosphorylation sites, DARPP-32 is an excellent coincidence detector and signal integrator, as many more protein kinases and phosphatases regulate the signaling properties of DARPP-32. Stimulants like ► amphetamines, ► nicotine, and ► caffeine all show impaired efficacy in transgenic mice with ablation or genetically diminished phosphorylation capacity of DARPP-32. Anti-psychotics like ► haloperidol that block dopamine receptors were also shown to affect DARPP-32 phosphorylation in the same direction as the above-described stimulants. The differential behavioral consequences induced by both classes of drugs may arise from cell-specificity in DARPP-32 phosphorylation as found in striatonigral versus striatopallidal neurons (Bateup et al. 2008). Several alternative explanations exist. The activation of the immediate early gene necessary for LTP maintenance, Arc/ Arg3.1, for example, needs simultaneous signaling of Gas-coupled receptors like dopamine D1 receptors, and calcium influx through NMDA receptors. It will need further studies to fully understand the interaction between dopaminergic and glutamatergic systems at the synaptic level.

Proteins involved in DARPP-32 signaling, especially PP1 and calcineurin, provide an interesting additional link between receptor function and synaptic plasticity via their modulation of the actin cytoskeleton in postsyn-aptic compartments.

Antidepressants, Mood Stabilizers, and Antidementia Drugs Modulate the Number of Dendritic Spines in the Hippocampus

The plasticity of synaptic morphology received much attention in recent years because of the technological revolution in genetic labeling and optical imaging. With two-photon, confocal, or evanescent wave imaging, it became possible to investigate single synapses at submicron resolution in unstained tissue. This development significantly accelerated studies on synaptic morphology that formerly required fixation and often electron microscopy. It was also the basis to identify a new downstream effector system of ► antidepressant drugs and the mood-stabilizer ► lithium in relation to synaptic plasticity: dendritic and post-synaptic morphology. This was first shown in a rodent model for depression, the bulbectomized rat. One of the anatomical consequences of bulbectomy is a decreased hippocampal volume. It could be shown that the ablation of the olfactory bulb, over a period of several weeks, induced a significant reduction in dendritic spines at glutamatergic neurons in the hippocampus. Loss of dendritic spines is thought to be equivalent to a loss of synaptic function. The antidepressant tianeptin was effectively protecting against spine loss in this animal model. Corroborating this finding, electron microscopy studies in ovariectomized rats found a similar increase in synapse number after short-term ► fluoxetine treatment, and sub-chronic treatment of ► imipramine was found to significantly modify synaptic morphology and increase dendritic spine density in hippocampal subregions of healthy adult rats. Increased expression of neurotrophic factors like BDNF may provide a mechanistic link between the monoaminergic system modulated by antidepressants and synaptic morphogens like filamentous actin. Tyrosine phosphorylation of b-catenin by BDNF is known to promote dissociation from cadherin, a major structural component of many synapses. Notably, b-catenin is also downstream of glycogen synthase kinase GSK-3b, the molecular target of mood stabilizers like lithium. Lithium treatment of stressed rats increased dendritic arborization of hippocampal pyramidal cells, also affecting the number of dendritic spines in this brain region (see also Pittenger and Duman 2008).

Dendritic spines can grow and collapse within minutes, and the NMDA receptor was shown to be a necessary trigger for such major though reversible changes in syn-aptic morphology. ► Memantine, one of the few available drugs for the treatment of ► Alzheimer's Disease (AD), acts as a partial NMDA receptor antagonist. In primary hippocampal cultures, memantine was shown to prevent dendritic spine loss and shape changes induced by oligomers of amyloid b (Calabrese et al. 2007), providing a potential mechanism for its therapeutic efficacy in AD patients. Beyond AD, the ► Fragile X Syndrome, the most common inherited cause of mental impairment and the most common known cause of autism, was linked to defects in synaptic plasticity. Lack of the Fragile X Mental Retardation Protein (FMRP) induces dysregula-tion of spine morphogenesis and exaggerated metabo-tropic glutamate receptor-dependent LTD. FMRP is a synaptic protein regulating dendritic RNA delivery and translational repression. Based on pharmacological and genetic experiments, current theories see FMRP and the metabotropic glutamate receptor 5 (mGluR5) as counterparts in dendritic protein synthesis. There is pre-clinical evidence that genetic suppression of mGluR5 or the mGluR5 antagonists MPEP and fenobam can re-balance the system at the physiological level and improve cognitive performance of mice lacking FMRP. This was corroborated by a pilot clinical trial with the mGluR5 antagonist fenobam (Berry-Kravis et al. 2009) and will followed up by further clinical studies using improved drugs from this new evolving class of psychoactive drugs.

Synaptic plasticity is not a phenomenon restricted to the postsynaptic part of neuronal synapses. In the example of amyloid b-induced spine collapse, presynaptic boutons have been also affected and spontaneous synaptic transmission impaired. Morphological changes of presynaptic structures currently are targets of numerous studies. Functional plasticity of presynaptic proteins is particularly important for LTP at GABAergic synapses and most forms of STP. This short-lasting form of plasticity is dependent on the vesicular release machinery and modulated by a number of mechanisms regulating pre-synaptic calcium (Zucker and Regehr 2002).

Nicotine Receptors Affect Short-term Plasticity by Regulation of Vesicular Transmitter release

Presynaptic nicotinic acetylcholine receptors (nAChR) are an important trigger for increased presynaptic calcium and have been shown to regulate STP in a number of brain areas. Particularly, the a7 nAChR channel is a target for a number of drug candidates currently in clinical development for the treatment of negative symptoms in ► schizophrenia or ► mild cognitive impairment. Those receptors are expressed in many neurons at presynaptic sites while they control as postsynaptic receptors on GABAergic neurons the inhibitory tone in the hippocampus. Presynaptically, there is strong evidence that nAChR control release probability of several neurotransmitters, notably also of ► dopamine. Earlier studies using tonic application of subtype selective nAChR agonists showed a role for non-a7 AChRs in the regulation of dopamine release. More recently, phasic and short-term activation pattern of synaptosomes revealed a significant role of a7 receptors in the control of the readily releasable pool of dopamine (Turner 2004). The increase in dopamine release upon phasic AChR stimulation was dependent on the calcium-binding protein calmodulin but not on pre-synaptic high-voltage-activated calcium channels, as was the case for the non-a7 receptor mediated dopamine release. An increase in the number of vesicles ready to release their neurotransmitter upon stimulation facilitates neurotransmission for the next few synaptic events, and thus represents a form of STP. Nicotinic a7 receptors show an agonist-dependent rapid and strong desensitiza-tion after activation, and this desensitization likely turns strongly desensitizing agonists such as nicotine into functional antagonists when they are constantly present. Partial a7 receptor agonists like MEM3454 from Memory Pharmaceuticals may well have a different effect due to their increased activation of a7 receptor mediated steady-state current. Still, a continuous presence of the drug may impair phasic cholinergic signaling via those receptors. In this respect, allosteric positive a7 receptor modulators are likely to keep ► phasic signal transmission intact and thus may show a stronger impact on synaptic facilitation at dopaminergic synapses and therapeutic efficacy.

In summary, there is good evidence that psychother-apeutics influence forms of synaptic plasticity beyond LTP and LTD. Whether changes of synaptic structure or function upon treatment with psychoactive drugs are purely coincidental or causally correlated with their therapeutic

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