Presynaptic Release Probability Is Increased in Hippocampal Neurons From ASIC1 Knockout Mice

Abstract

Cho J-H, Askwith CC. Presynaptic release probability is increased in hippocampal neurons from ASIC1 knockout mice. J Neurophysiol 99: 426 -441, 2008. First published December 19, 2007 doi:10.1152/jn.00940.2007. Acid-sensing ion channels (ASICs) are H ϩ -gated channels that produce transient cation currents in response to extracellular acid. ASICs are expressed in neurons throughout the brain, and ASIC1 knockout mice show behavioral impairments in learning and memory. The role of ASICs in synaptic transmission, however, is not thoroughly understood. We analyzed the involvement of ASICs in synaptic transmission using microisland cultures of hippocampal neurons from wild-type and ASIC knockout mice. There was no significant difference in single action potential (AP)-evoked excitatory postsynaptic currents (EPSCs) between wild-type and ASIC knockout neurons. However, paired-pulse ratios (PPRs) were reduced and spontaneous miniature EPSCs (mEPSCs) occurred at a higher frequency in ASIC1 knockout neurons compared with wildtype neurons. The progressive block of NMDA receptors by an open channel blocker, MK-801, was also faster in ASIC1 knockout neurons. The amplitude and decay time constant of mEPSCs, as well as the size and refilling of the readily releasable pool, were similar in ASIC1 knockout and wild-type neurons. Finally, the release probability, which was estimated directly as the ratio of AP-evoked to hypertonic sucrose-induced charge transfer, was increased in ASIC1 knockout neurons. Transfection of ASIC1a into ASIC1 knockout neurons increased the PPRs, suggesting that alterations in release probability were not the result of developmental compensation within the ASIC1 knockout mice. Together, these findings demonstrate that neurons from ASIC1 knockout mice have an increased probability of neurotransmitter release and indicate that ASIC1a can affect presynaptic mechanisms of synaptic transmission.

Identification of Protein Domains That Control Proton and Calcium Sensitivity of ASIC1a

“…Most modulators of ASIC1a function, including zinc, redox reagents, lactate, and PcTx1, act by altering the apparent proton sensitivity of the channel (16,18,25,(31)(32)(33)(34). These compounds also impact ASIC1a-induced neuronal death (8,9,15,31).…”

Cell Type-Specific Expression of Acid-Sensing Ion Channels in Hippocampal Interneurons

“…Many studies showed that GABAergic inhibitory interneurons in the hippocampus have larger ASIC current densities than glutamatergic excitatory pyramidal neurons (PNs) (Bolshakov et al, 2002;Cho and Askwith, 2008;Ziemann et al, 2008). In line with this view, a recent report showed that ASIC1a null mice display delayed seizure termination after seizure induction and suggested that ASIC activation by falls in extracellular pH during seizures increases the cortical inhibition through preferential recruitment of GABAergic inhibitory interneurons (Ziemann et al, 2008).…”

Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala

“…In previous studies of hippocampal brain slices, extracellular field potential recordings suggested impaired hippocampal long-term potentiation (LTP) in ASIC1a −/− mice (20), although another study did not detect an effect of ASIC1a (33). Another study using microisland cultures of hippocampal neurons suggested that the probability of neurotransmitter release increased in ASIC1a −/− mice (32).…”

“…Although these observations raised the possibility that protons might be a neurotransmitter, postsynaptic ASIC currents have not been detected in cultured hippocampal neurons (31,32), and whether localized pH transients might play a signaling role in neuronal communication remains unclear. In previous studies of hippocampal brain slices, extracellular field potential recordings suggested impaired hippocampal long-term potentiation (LTP) in ASIC1a −/− mice (20), although another study did not detect an effect of ASIC1a (33).…”