Presynaptic cholinergic neuromodulation alters the temporal dynamics of short-term depression at parvalbumin-positive basket cell synapses from juvenile CA1 mouse hippocampus

Abstract

Parvalbumin-positive basket cells (PV BCs) of the CA1 hippocampus are active participants in theta (5-12 Hz) and gamma (20-80 Hz) oscillations in vivo. When PV BCs are driven at these frequencies in vitro, inhibitory postsynaptic currents (IPSCs) in synaptically connected CA1 pyramidal cells exhibit paired-pulse depression (PPD) and multiple-pulse depression (MPD). Moreover, PV BCs express presynaptic muscarinic acetylcholine receptors (mAChRs) that may be activated by synaptically released acetylcholine during learning behaviors in vivo. Using acute hippocampal slices from the CA1 hippocampus of juvenile PV-GFP mice, we performed whole cell recordings from synaptically connected PV BC-CA1 pyramidal cell pairs to investigate how bath application of 10 μM muscarine impacts PPD and MPD at CA1 PV BC-pyramidal cell synapses. In accordance with previous studies, PPD and MPD magnitude increased with stimulation frequency. mAChR activation reduced IPSC amplitude and transiently reduced PPD, but MPD was largely maintained. Consistent with a reduction in release probability (pr), MPD and mAChR activation increased both the coefficient of variation of IPSC amplitudes and the fraction of failures. Using variance-mean analysis, we converted MPD trains to pr functions and developed a kinetic model that optimally fit six distinct pr conditions. The model revealed that vesicular depletion caused MPD and that recovery from depression was dependent on calcium. mAChR activation reduced the presynaptic calcium transient fourfold and initial pr twofold, thereby reducing PPD. However, mAChR activation slowed calcium-dependent recovery from depression during sustained repetitive activity, thereby preserving MPD. Thus the activation of presynaptic mAChRs optimally protects PV BCs from vesicular depletion during short bursts of high-frequency activity.

A kinetic model for the frequency dependence of cholinergic modulation at hippocampal GABAergic synapses

“…In the experiments that we model in this paper, whole-cell recordings are performed from synaptically connected pairs of neurons in mouse hippocampal slices from GFP-positive PV mice [39]. The presynaptic neuron was a PV basket cell (BC) and the postsynaptic neuron was a CA1 pyramidal cell (PC).…”

“…N and q were obtained from the parabolic fit, and were determined to be N = 12.6 ±3.4 (active release sites) and q = 33.8 ± 4.8 pA (per active release site) [39]. …”

“…Similarly, coefficient of variation and failures analysis indicated that at CA1 PV BC synapses, STP was of presynaptic origin [39]. When an action potential arrives at the BC presynaptic terminal, P/Q-type calcium channels open [30], and an influx of calcium induces exocytosis of vesicles into the synaptic cleft.…”

“…Here, using paired recordings between CA1 PV basket cells and pyramidal cells [39] and a mathematical model unifying synaptic depression and facilitation developed by Dittman [18, 19] and expanded upon by Lee [40], we examine underlying mechanisms of STP at hippocampal CA1 PV basket cell synapses across a broad range of physiologically relevant firing frequencies [59, 35]. Activity-dependent synaptic depression in the data is shown to be completely accounted for by vesicular depletion, with minimal contribution of synaptic facilitation due to the rapid decay of presynaptic calcium concentration.…”

Evidence for M2 muscarinic receptor modulation of axon terminals and dendrites in the rodent basolateral amygdala: An ultrastructural and electrophysiological analysis

“…The extent of muscarinic inhibition of the IPSC in BLa is somewhat less that the 71% reported in hippocampus using carbachol (Behrends and ten Bruggencate, 1993), but similar to that reported in entorhinal cortex using muscarine (Apergis-Schoute et al, 2007). In hippocampus, M 2 Rs are preferentially expressed on terminals of PV+ basket cells, where they play a powerful role in regulating IPSCs in PNs (Hájos et al 1998; Fukudome et al 2004; Lawrence et al, 2015). Similarly, in BLa we found that a majority (58%) of the M 2 Rs are on PV+ terminals.…”