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Levetiracetam Reverses Psilocybin Induced Increase in SV2A: Possible Role in the Etiology and Treatment of HPPD

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Before we get into the significance of this connection, we must first learn a little bit about what Levetiracetam and SV2A are. click (LINK) for links.



In 1999, Levetiracetam (LEV—commercial name: Keppra©) was approved by the Food and Drug administration as a novel anti-epileptic drug. It is particularly useful in patients suffering from partial seizures, patients less responsive to conventional drugs or showing risks of drug interactions (Hovinga, 2001). Even if the exact mechanism by which LEV acts on seizures is still undefined (we don’t even known if LEV is an agonist or antagonist of SV2A), we know that it binds to SV2A and that this binding is required for its anti-epileptic action (Lynch et al., 2004). Implicated residues in this binding are depicted in Figure 4 (Shi et al., 2011Lee et al., 2015). It is worth noting that LEV is able to normalize under- and over-expression of SV2A in autaptic hippocampal neurons by controlling the concentration of SV2A in the synapse (Nowack et al., 2011). More recently, other compounds were added to the racetam family—Brivaracetam, Selectracetam—and show promises for epilepsy therapeutic control. (LINK)


The major mechanism of action of LEV is considered to involve binding to synaptic vesicle glycoprotein 2A (Lynch et al., 2004), although other pharmacological actions have also been demonstrated, such as inhibition of N‐type voltage‐sensitive Ca2+ and K+ channelsAMPA receptors and Ca2+ release from intracellular Ca2+ stores mediated by inositol 1,4,5‐trisphosphate (IP3) receptors (Carunchio et al., 2007; De Smedt et al., 2007b; Fukuyama et al., 2012). In particular, activation of the AMPA receptor plays important roles in the initiation of epileptic seizures and propagation of epileptic discharge (Rogawski, 2002), whereas hyper‐activation of the IP3 receptor contributes to the neuronal damage induced by epileptic seizure, seizure maintenance and dysfunction of GABA exocytosis during epileptic discharge (Pal et al., 2001; Fukuyama et al., 2012). (link)



SV2A belongs to the Synaptic vesicle (SV) protein 2 family, which also includes SV2B and SV2C. These three paralogs can be found in vesicles of neuronal or endocrine cells. SV2A is the only member of the SV2 family ubiquitously expressed in the adult brain, and is also found in neuroendocrine cells and at neuromuscular junctions (Buckley and Kelly, 1985Bajjalieh et al., 1994Dong et al., 2006).  SV2A is found in all areas of the brain, including the trigeminal nuclei (Edvinsson et al., 2015) and the sphenopalatine ganglion (Steinberg et al., 2016) where it was recently found. (LINK)


One of the first trials on the role of SV2A was the extreme phenotype displayed by SV2A KO mice. Mice that survive birth seem to be normal during their first days of life. However, after 1–2 weeks, they experience seizures, quickly followed by weight loss and death around P20 (Crowder et al., 1999Janz et al., 1999). (LINK)


A more recent electrophysiological study performed on hippocampal slices showed that in the absence of SV2A, EPSC amplitudes remain unchanged while the associated frequencies increase (Venkatesan et al., 2012). The author emphasized that the opposite effect of SV2A on excitatory and inhibitory currents observed in hippocampal slices of SV2A KO likely underlines an effect of SV2A on GABAergic network subsequently impacting the Glutamatergic synapses rather than a direct effect of SV2A on both networks. Interestingly, overexpression of SV2A in autaptic hippocampal neurons produced the typical neurotransmission defect observed in SV2A KO mice (Nowack et al., 2011). (x) Mice models where higher levels of SV2A are found, experience “evoked” seizures in response to convulsing chemicals or mild electrical stimulations rather than real spontaneous seizures (Sharma et al., 2007). (LINK)




Now-- On to the show :)



A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n=6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n=6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.4% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (-15.21% to -50.19%). These differences were statistically significant in the hippocampus for all radioligands and in PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in hippocampus (+9.24%) and PFC (+6.1%) whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin’s antidepressive actions are linked to increased persistent synaptogenesis and possibly also to an acute decrease in 5-HT2AR density.


Levetiracetam Reverses Synaptic Deficits Produced by Overexpression of SV2A

Levetiracetam is an FDA-approved drug used to treat epilepsy and other disorders of the nervous system. Although it is known that levetiracetam binds the synaptic vesicle protein SV2A, how drug binding affects synaptic functioning remains unknown. Here we report that levetiracetam reverses the effects of excess SV2A in autaptic hippocampal neurons. Expression of an SV2A-EGFP fusion protein produced a ∼1.5-fold increase in synaptic levels of SV2, and resulted in reduced synaptic release probability. The overexpression phenotype parallels that seen in neurons from SV2 knockout mice, which experience severe seizures. Overexpression of SV2A also increased synaptic levels of the calcium-sensor protein synaptotagmin, an SV2-binding protein whose stability and trafficking are regulated by SV2. Treatment with levetiracetam rescued normal neurotransmission and restored normal levels of SV2 and synaptotagmin at the synapse. These results indicate that changes in SV2 expression in either direction impact neurotransmission, and suggest that levetiracetam may modulate SV2 protein interactions.


TLDR: Mushrooms increase SV2A. Levetiracetam "normalizes" SV2A. Although we cannot assume causation, this correlation may have something to do with the etiology and treatment of HPPD. 


More to come :)


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