Abstract
Tonic GABAergic inhibition regulates neuronal excitability and has been implicated to be involved in both neurological and psychiatric diseases. We have previously shown that the endogenous peptide antisecretory factor (AF) decreases phasic GABAergic inhibition onto pyramidal CA1 neurons. In the present study, using whole-cell patch-clamp recordings, we investigated the mechanisms behind this disinhibition of CA1 pyramidal neurons by AF. We found that application of AF to acute rat hippocampal slices resulted in a reduction of the frequency, but not of the amplitude, of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. Miniature inhibitory postsynaptic currents (mIPSCs), recorded in the presence of tetrodotoxin (TTX), were however not affected by AF, neither in CA1 pyramidal cells, nor in stratum radiatum interneurons. Instead, AF caused an increase of the tonic GABAA current in stratum radiatum interneurons, leaving the tonic GABAergic transmission in CA1 pyramidal cells unaffected. These results show that the endogenous peptide AF enhances tonic, but not phasic, GABAergic signaling in CA1 stratum radiatum interneurons, without affecting tonic GABAergic signaling in CA1 pyramidal neurons. We suggest that this increased tonic GABAergic signaling in GABAergic interneurons could be a mechanism for the AF-mediated disinhibition of pyramidal neurons.
Highlights
Antisecretory factor (AF) is an endogenous 43 kDa protein that is expressed in all mammalian tissues and plasma investigated so far (Johansson et al, 1995, 2009; Lange et al, 1999; Lange and Lönnroth, 2001; Ulgheri et al, 2010)
In the present study, using whole-cell patch clamp recordings, we further examined the effect of AF-16 on GABAergic inhibition onto CA1 pyramidal neurons
We first investigated spontaneous action potential-dependent spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. 50–60 min after applying AF-16 to the hippocampal slice there was a decrease in the frequency of sIPSCs to 78 ± 7% (p < 0.05, paired t-test) of the frequency obtained prior to the application, without a significant change in the averaged amplitude 95 ± 7% (p = 0.52, paired t-test) of the sIPSCs (n = 8) (Figure 1A)
Summary
Antisecretory factor (AF) is an endogenous 43 kDa protein that is expressed in all mammalian tissues and plasma investigated so far (Johansson et al, 1995, 2009; Lange et al, 1999; Lange and Lönnroth, 2001; Ulgheri et al, 2010). The protein was named AF due to its capacity to counteract enterotoxin-induced intestinal hypersecretion, but later studies have shown that AF is a potent anti-inflammatory agent (Johansson et al, 1997a, 2013; Eriksson et al, 2003; Davidson and Hickey, 2004a,b; Graber et al, 2011; Mane et al, 2011). Protein AF, which is named S5a or RPn10, is a component of the 26S proteasome (Ulgheri et al, 2010). AF has been demonstrated to counteract various forms of intestinal hypersecretion in clinical studies, and a number of experimental studies have demonstrated a protective, regulating effect of AF-16 in various models of tissue injury
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