Presynaptic α7 Nicotinic Acetylcholine Receptors Enhance Hippocampal Mossy Fiber Glutamatergic Transmission via PKA Activation

Abstract

Nicotinic acetylcholine receptors (nAChRs) are expressed widely in the CNS, and mediate both synaptic and perisynaptic activities of endogenous cholinergic inputs and pharmacological actions of exogenous compounds (e.g., nicotine and choline). Behavioral studies indicate that nicotine improves such cognitive functions as learning and memory. However, the mechanism of nicotine's action on cognitive function remains elusive. We performed patch-clamp recordings from hippocampal CA3 pyramidal neurons to determine the effect of nicotine on mossy fiber glutamatergic synaptic transmission. We found that nicotine in combination with NS1738, an ␣7 nAChR-positive allosteric modulator, strongly potentiated the amplitude of evoked EPSCs (eEPSCs), and reduced the EPSC paired-pulse ratio. The action of nicotine and NS1738 was mimicked by PNU-282987 (an ␣7 nAChR agonist), and was absent in ␣7 nAChR knock-out mice. These data indicate that activation of ␣7 nAChRs was both necessary and sufficient to enhance the amplitude of eEPSCs. BAPTA applied postsynaptically failed to block the action of nicotine and NS1738, suggesting again a presynaptic action of the ␣7 nAChRs. We also observed ␣7 nAChR-mediated calcium rises at mossy fiber giant terminals, indicating the presence of functional ␣7 nAChRs at presynaptic terminals. Furthermore, the addition of PNU-282987 enhanced action potential-dependent calcium transient at these terminals. Last, the potentiating effect of PNU-282987 on eEPSCs was abolished by inhibition of protein kinase A (PKA). Our findings indicate that activation of ␣7 nAChRs at presynaptic sites, via a mechanism involving PKA, plays a critical role in enhancing synaptic efficiency of hippocampal mossy fiber transmission.

Nicotinic ACh receptors as therapeutic targets in CNS disorders

“…This information will provide further insight into the development of therapeutic treatments for the cognitive impairments associated with schizophrenia. Along these lines, we recently found that presynaptic α7 * nAChRs, via a mechanism involving PKA, enhanced hippocampal CA3 mossy fiber glutamatergic transmission [147]. These types of studies may help to provide a mechanistic explanation for the hypothesis that nicotine enhances the mossy fiber glutamatergic transmission in the hippocampal CA3 region to compensate for a loss of synaptic connection in schizophrenic patients [148].…”

The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function

“…Highest expression is found in hippocampus, cingulate gyrus, lateral and medial geniculates, and the reticular nucleus of the thalamus (RTN). In hippocampus, α7nAChR-mediated release of glutamate is enhanced by the activity of protein kinase A (PKA) (Cheng and Yakel, 2014). Protein kinase A expression appears to be permanently up regulated in postmortem brain of smokers (Hope et al, 2007).…”

Looking below the surface of nicotinic acetylcholine receptors

“…However, in many cases it is not clear whether the receptor itself is the phosphoprotein. Likewise, when receptor activation has been implicated to regulate kinase activity, it is usually assumed that channel-mediated currents (usually calcium) are required intermediates to phosphorylation events (Chatterjee et al, 2009, Cheng and Yakel, 2014, El Kouhen et al, 2009, Gubbins et al, 2010, Marrero and Bencherif, 2009, Nuutinen et al, 2006, Ren et al, 2005). Although there have been studies that have shown nAChR to be phosphorylated (Charpantier et al, 2005, Guo and Wecker, 2002, Pollock et al, 2009, Pollock et al, 2007) and their phosphorylation status to have effects on turnover, assembly, and subcellular localization (Hopfield et al, 1988, Huganir et al, 1986, Swope et al, 1999) (Yamada et al, 2010), the question remains: to what degree is there direct functional cross talk between phosphorylation sites in the intracellular domain and extracellular and transmembrane sites that regulate channel function?…”