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Cholinergic afferent stimulation induces axonal function plasticity in adult hippocampal granule cells.

Martinello K, Huang Z, Lujan R, Tran B, Watanabe M, Cooper EC, Brown DA, Shah MM - Neuron (2015)

Bottom Line: The effects of acetylcholine on axonal information processing, though, remain unknown.In support, immunohistochemistry revealed muscarinic M1 receptor, CaV3.2, and KV7.2/7.3 subunit localization in granule cell axons.Since alterations in axonal signaling affect neuronal firing patterns and neurotransmitter release, this is an unreported cellular mechanism by which acetylcholine might, at least partly, enhance cognitive processing.

View Article: PubMed Central - PubMed

Affiliation: UCL School of Pharmacy, University College London, London, WC1N 1AX, UK.

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Enhanced T-Type Ca2+ Channel Activity Is Required for Muscarinic Receptor-Mediated Persistent Spike Threshold Reduction and KV7/M Current Suppression(Ai and Avi) Example traces under control conditions, in the presence of the TTA-P2 (500 nM), either co-application of TTA-P2 and Oxo-M (1 μM) or following HF stimulation in the presence of TTA-P2 and 25 min post-treatment. The RMP values are next to the traces. The insets show 1 s of each trace on an expanded scale. The scales apply to all traces.(Aii, Aiii, Aiv, Av, and Avii) The action potentials numbers (AP No.) under control conditions, in the presence of a voltage-gated Ca2+ channel inhibitors (VGCCI), in the presence of the VCCI either following 10 min Oxo-M treatment or HF stimulation and 25 min post-treatment.(Bi) Representative single spikes and phase plane plots before and after Oxo-M treatment when TTA-P2 was present.(Bii) The average spike threshold under control conditions, in the presence of the VCCI and pre- and post-treatment with the VCCI.(Ci) Example perforated-patch voltage-clamp traces obtained when the de-activation protocol was applied under control conditions, in the presence of TTA-P2, following a 10 min co-application of TTA-P2 and Oxo-M and subsequent application of XE991 (3 μM).(Cii) The traces obtained in the presence of XE991 were subtracted from all other traces to obtain the KV7/M currents.(Ciii) The average KV7/M current (IM) amplitude obtained by hyperpolarizing to −50 mV from −20 mV.(Civ) The apparent activation curve for the KV7/M currents under control conditions, in the presence of TTA-P2 and during co-application of TTA-P2 and Oxo-M.
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fig6: Enhanced T-Type Ca2+ Channel Activity Is Required for Muscarinic Receptor-Mediated Persistent Spike Threshold Reduction and KV7/M Current Suppression(Ai and Avi) Example traces under control conditions, in the presence of the TTA-P2 (500 nM), either co-application of TTA-P2 and Oxo-M (1 μM) or following HF stimulation in the presence of TTA-P2 and 25 min post-treatment. The RMP values are next to the traces. The insets show 1 s of each trace on an expanded scale. The scales apply to all traces.(Aii, Aiii, Aiv, Av, and Avii) The action potentials numbers (AP No.) under control conditions, in the presence of a voltage-gated Ca2+ channel inhibitors (VGCCI), in the presence of the VCCI either following 10 min Oxo-M treatment or HF stimulation and 25 min post-treatment.(Bi) Representative single spikes and phase plane plots before and after Oxo-M treatment when TTA-P2 was present.(Bii) The average spike threshold under control conditions, in the presence of the VCCI and pre- and post-treatment with the VCCI.(Ci) Example perforated-patch voltage-clamp traces obtained when the de-activation protocol was applied under control conditions, in the presence of TTA-P2, following a 10 min co-application of TTA-P2 and Oxo-M and subsequent application of XE991 (3 μM).(Cii) The traces obtained in the presence of XE991 were subtracted from all other traces to obtain the KV7/M currents.(Ciii) The average KV7/M current (IM) amplitude obtained by hyperpolarizing to −50 mV from −20 mV.(Civ) The apparent activation curve for the KV7/M currents under control conditions, in the presence of TTA-P2 and during co-application of TTA-P2 and Oxo-M.

Mentions: Since the spike threshold effects occur at rest (Figure 1B), the VGCCs involved are likely to be low-threshold channels such as T-, R-, and L-type Ca2+ channels (Catterall, 2011). Interestingly, in CA1 neurons, muscarinic receptor stimulation enhances R-type Ca2+ channel activity (Park and Spruston, 2012). In granule cells, though, the T-type Ca2+ channel inhibitors, NiCl2 (50 μM) and TTA-P2 (500 nM) (Dreyfus et al., 2010), but not the R-and L-type Ca2+ channel inhibitors, SNX482 (500 nM) and nifedipine (10 μM), prevented the Oxo-M-induced sustained action potential firing and threshold change (Figure 6). All auxiliary effects of Oxo-M (depolarized RMP, enhanced RN, and ADP generation) still occurred, leading to a reversible increase in action potential firing (Figure 6A, Table S2). TTA-P2 also prevented the effects of HF cholinergic afferent stimulation on granule cell excitability (Figure 6, Table S2) but had little effect on cholinergic EPSP amplitude or summation (summation ratio = 2.50 ± 0.36, n = 5).


Cholinergic afferent stimulation induces axonal function plasticity in adult hippocampal granule cells.

Martinello K, Huang Z, Lujan R, Tran B, Watanabe M, Cooper EC, Brown DA, Shah MM - Neuron (2015)

Enhanced T-Type Ca2+ Channel Activity Is Required for Muscarinic Receptor-Mediated Persistent Spike Threshold Reduction and KV7/M Current Suppression(Ai and Avi) Example traces under control conditions, in the presence of the TTA-P2 (500 nM), either co-application of TTA-P2 and Oxo-M (1 μM) or following HF stimulation in the presence of TTA-P2 and 25 min post-treatment. The RMP values are next to the traces. The insets show 1 s of each trace on an expanded scale. The scales apply to all traces.(Aii, Aiii, Aiv, Av, and Avii) The action potentials numbers (AP No.) under control conditions, in the presence of a voltage-gated Ca2+ channel inhibitors (VGCCI), in the presence of the VCCI either following 10 min Oxo-M treatment or HF stimulation and 25 min post-treatment.(Bi) Representative single spikes and phase plane plots before and after Oxo-M treatment when TTA-P2 was present.(Bii) The average spike threshold under control conditions, in the presence of the VCCI and pre- and post-treatment with the VCCI.(Ci) Example perforated-patch voltage-clamp traces obtained when the de-activation protocol was applied under control conditions, in the presence of TTA-P2, following a 10 min co-application of TTA-P2 and Oxo-M and subsequent application of XE991 (3 μM).(Cii) The traces obtained in the presence of XE991 were subtracted from all other traces to obtain the KV7/M currents.(Ciii) The average KV7/M current (IM) amplitude obtained by hyperpolarizing to −50 mV from −20 mV.(Civ) The apparent activation curve for the KV7/M currents under control conditions, in the presence of TTA-P2 and during co-application of TTA-P2 and Oxo-M.
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fig6: Enhanced T-Type Ca2+ Channel Activity Is Required for Muscarinic Receptor-Mediated Persistent Spike Threshold Reduction and KV7/M Current Suppression(Ai and Avi) Example traces under control conditions, in the presence of the TTA-P2 (500 nM), either co-application of TTA-P2 and Oxo-M (1 μM) or following HF stimulation in the presence of TTA-P2 and 25 min post-treatment. The RMP values are next to the traces. The insets show 1 s of each trace on an expanded scale. The scales apply to all traces.(Aii, Aiii, Aiv, Av, and Avii) The action potentials numbers (AP No.) under control conditions, in the presence of a voltage-gated Ca2+ channel inhibitors (VGCCI), in the presence of the VCCI either following 10 min Oxo-M treatment or HF stimulation and 25 min post-treatment.(Bi) Representative single spikes and phase plane plots before and after Oxo-M treatment when TTA-P2 was present.(Bii) The average spike threshold under control conditions, in the presence of the VCCI and pre- and post-treatment with the VCCI.(Ci) Example perforated-patch voltage-clamp traces obtained when the de-activation protocol was applied under control conditions, in the presence of TTA-P2, following a 10 min co-application of TTA-P2 and Oxo-M and subsequent application of XE991 (3 μM).(Cii) The traces obtained in the presence of XE991 were subtracted from all other traces to obtain the KV7/M currents.(Ciii) The average KV7/M current (IM) amplitude obtained by hyperpolarizing to −50 mV from −20 mV.(Civ) The apparent activation curve for the KV7/M currents under control conditions, in the presence of TTA-P2 and during co-application of TTA-P2 and Oxo-M.
Mentions: Since the spike threshold effects occur at rest (Figure 1B), the VGCCs involved are likely to be low-threshold channels such as T-, R-, and L-type Ca2+ channels (Catterall, 2011). Interestingly, in CA1 neurons, muscarinic receptor stimulation enhances R-type Ca2+ channel activity (Park and Spruston, 2012). In granule cells, though, the T-type Ca2+ channel inhibitors, NiCl2 (50 μM) and TTA-P2 (500 nM) (Dreyfus et al., 2010), but not the R-and L-type Ca2+ channel inhibitors, SNX482 (500 nM) and nifedipine (10 μM), prevented the Oxo-M-induced sustained action potential firing and threshold change (Figure 6). All auxiliary effects of Oxo-M (depolarized RMP, enhanced RN, and ADP generation) still occurred, leading to a reversible increase in action potential firing (Figure 6A, Table S2). TTA-P2 also prevented the effects of HF cholinergic afferent stimulation on granule cell excitability (Figure 6, Table S2) but had little effect on cholinergic EPSP amplitude or summation (summation ratio = 2.50 ± 0.36, n = 5).

Bottom Line: The effects of acetylcholine on axonal information processing, though, remain unknown.In support, immunohistochemistry revealed muscarinic M1 receptor, CaV3.2, and KV7.2/7.3 subunit localization in granule cell axons.Since alterations in axonal signaling affect neuronal firing patterns and neurotransmitter release, this is an unreported cellular mechanism by which acetylcholine might, at least partly, enhance cognitive processing.

View Article: PubMed Central - PubMed

Affiliation: UCL School of Pharmacy, University College London, London, WC1N 1AX, UK.

Show MeSH
Related in: MedlinePlus