Mechanisms Generating Dual-Component Nicotinic EPSCs in Cortical Interneurons

Abstract

Activation of cortical nicotinic receptors by cholinergic axons from the basal forebrain (BF) significantly impacts cortical function, and the loss of nicotinic receptors is a hallmark of aging and neurodegenerative disease. We have previously shown that stimulation of BF axons generates a fast α7 and a slow non-α7 receptor-dependent response in cortical interneurons. However, the synaptic mechanisms that underlie this dual-component nicotinic response remain unclear. Here, we report that fast α7 receptor-mediated EPSCs in the mouse cortex are highly variable and insensitive to perturbations of acetylcholinesterase (AChE), while slow non-α7 receptor-mediated EPSCs are reliable and highly sensitive to AChE activity. Based on these data, we propose that the fast and slow nicotinic responses reflect differences in synaptic structure between cholinergic varicosities activating α7 and non-α7 classes of nicotinic receptors.

Orexin-dependent activation of layer VIb enhances cortical network activity and integration of non-specific thalamocortical inputs

“…These receptors coexist with homomeric a7 receptors in GAD? layer VIb neurons, as reported in layers I-V interneurons (Porter et al 1999;Christophe et al 2002;Arroyo et al 2012;Bennett et al 2012). Electrophysiological detection of orexin and nicotinic receptors appeared to be more sensitive than detection of their mRNAs by scPCR, consistent with previous observations, in particular for neuropeptide receptors (Gallopin et al 2006;Ferezou et al 2007;Hu et al 2011).…”

Nicotinic acetylcholine receptor-mediated responses in medial vestibular and prepositus hypoglossi nuclei neurons showing distinct neurotransmitter phenotypes

“…Because volume transmission occurs at the extrasynaptic membrane, the time course of the transmission is extremely slow. In addition, volume transmission is known to be mediated primarily via ␣4␤2 nAChRs (Bennett et al 2012;Ren et al 2011). In the present study, the plots of the 10%-90% rise times against the half-widths revealed a wide distribution of Sand FS-type responses.…”

“…In addition to conventional cholinergic synaptic transmission, ACh is also used for nonsynaptic transmission known as "volume transmission" (Bennett et al 2012;Lendvai and Vizi 2008;Sarter et al 2009). Because volume transmission occurs at the extrasynaptic membrane, the time course of the transmission is extremely slow.…”

“…Most nAChRs expressed in the CNS are either of the ␣7 subtype, which exhibits fast decay kinetics, low affinity for ACh, and high Ca 2ϩ permeability, or of the non-␣7 (predominantly ␣4␤2) subtypes, which exhibit relatively slow decay kinetics and high ACh affinity (Chen and Patrick 1997;Flores et al 1992;Holladay et al 1997;Lindstrom et al 1995). In addition to their distinct properties, it has been suggested that ␣7 and non-␣7 subtypes participate in the distinct cholinergic transmissions, such as ␣7-mediated conventional synaptic transmission and non-␣7-mediated nonsynaptic transmission (volume transmission; Bennett et al, 2012). Therefore, elucidating which nAChRs subtypes are expressed in specific neurons can provide important clues for understanding nAChR-mediated cholinergic transmission.…”

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Projections from the basal forebrain innervate the cortex, and release of ACh was found to stimulate a7 and non-a7 nAChRs that are preferentially expressed on interneurons of the different cortical layers . MLA blocked fast neurotransmission indicative of the a7 nAChR contribution, whereas slow, non-a7 nAChR transmission was blocked by DHbE, with some cells showing a dual fast and slow component Bennett et al, 2012). Cholinergic modulation of interneuronal activity was shown to participate in signal processing and the formation of LTP when the presynaptic cell was stimulated and postsynaptic cell was hyperpolarized (Griguoli et al, 2013).…”