VIP enhances both pre‐ and postsynaptic GABAergic transmission to hippocampal interneurones leading to increased excitatory synaptic transmission to CA1 pyramidal cells

Vasoactive intestinal peptide (VIP) is present in the hippocampus in three subtypes of GABAergic interneurones, two of which innervate preferentially other interneurones, responsible for pyramidal cell inhibition. We investigated how pre- and postsynaptic modulation of GABAergic transmission (to both pyramidal cells and interneurones) by VIP could influence excitatory synaptic transmission in the CA1 area of the hippocampus. VIP (0.1–100 nM) increased [3H]GABA release from hippocampal synaptosomes (maximum effect at 1 nM VIP; 63.8±4.0%) but did not change [3H]glutamate release. VIP (0.3–30 nM) enhanced synaptic transmission in hippocampal slices (maximum effect at 1 nM VIP; field excitatory postsynaptic potentials (epsp) slope: 23.7±1.1%; population spike amplitude: 20.3±1.7%). The action on field epsp slope was fully dependent on GABAergic transmission since it was absent in the presence of picrotoxin (50 μM) plus {"type":"entrez-protein","attrs":{"text":"CGP55845","term_id":"875097176","term_text":"CGP55845"}}CGP55845 (1 μM). VIP (1 nM) did not change paired-pulse facilitation but increased paired-pulse inhibition in CA1 pyramidal cells (16.0±0.9%), reinforcing the involvement of GABAergic transmission in the action of VIP. VIP (1 nM) increased muscimol-evoked inhibitory currents by 36.4±8.7% in eight out of ten CA1 interneurones in the stratum radiatum. This suggests that VIP promotes increased inhibition of interneurones that control pyramidal cells, leading to disinhibition of synaptic transmission to pyramidal cell dendrites. In conclusion, concerted pre- and postsynaptic actions of VIP lead to disinhibition of pyramidal cell dendrites causing an enhancement of synaptic transmission. Keywords: VIP, GABA, interneurones, hippocampus, rat, slices, patch clamp, synaptosomes Introduction Vasoactive intestinal peptide (VIP) is expressed in the hippocampus only in interneurones (Acsady et al., 1996a), suggesting that it might be involved in regulation of hippocampal GABAergic transmission. Three distinct subtypes of VIP-immunoreactive interneurones have been described (Acsady et al., 1996a, 1996b), having differential target selectivity. One consists of basket cells, responsible for somatic pyramidal cell inhibition, that are also immunoreactive for cholecystokinin (VIP/CCK-immunoreactive basket cells). The two other subtypes innervate selectively interneurones either at the stratum Oriens/Alveus border or at the stratum radiatum. These target neurones control synaptic transmission to pyramidal cells at distal dendrites in the stratum lacunosum-moleculare and proximal dendrites in the stratum radiatum, respectively (Acsady et al., 1996b). All classes of VIP-immunoreactive interneurones are innervated by serotonergic fibres from the median raphe nucleus (Papp et al., 1999) and also by GABAergic septal afferents like virtually all interneurone subtypes in the hippocampus (Freund & Antal, 1988; Papp et al., 1999). In addition, VIP/CCK-immunoreactive basket cells receive afferents from CA3 Schaffer collaterals (Acsady et al., 1996a) and are avoided by cholinergic septal afferents (Papp et al., 1999). VIP-immunoreactive interneurone-selective cells in the CA1 and CA3 areas also appear to receive input from the enthorhinal cortex projection to the stratum lacunosum-moleculare, since their main dendritic arborization is located in this layer (Acsady et al., 1996a). VIP acts through activation of two VIP-selective receptors: VPAC1 and VPAC2 receptors (see Harmar et al., 1998 for review), both positively coupled to adenylate cyclase. Both receptor subtypes have been identified in the hippocampus by autoradiography (Vertongen et al., 1997). VIP was shown to increase excitability of hippocampal pyramidal cells essentially through reduction of the Ca2+- and cAMP-dependent K+ conductance, leading to a decrease of the long-lasting afterhyperpolarization and the accommodation of firing (Haas & Gahwiler, 1992). This action is postsynaptic since it prevailed in low-Ca2+ – high-Mg2+ medium. VIP was also shown to increase the frequency of miniature ipscs to cultured pyramidal neurones without affecting their amplitude (Wang et al., 1997), suggesting a presynaptic action of VIP in the control of GABA release. These actions of VIP seem contradictory since they lead to opposing actions on pyramidal cell excitability. Yanovski et al. (1997) studied the influence of VIP application to one subtype of interneurones targeted by VIP-immunoreactive interneurones that are located at the Oriens/Alveus border. In the absence of synaptic interactions, VIP (100 nM, in the bath) increased the firing rate of these interneurones. In the same study, local application of VIP (10 μM; pressure applied) to the Oriens/Alveus border decreased the slope of field excitatory postsynaptic potentials (epsps) recorded in the stratum radiatum and stratum lacunosum-moleculare. VIP thus led to a decrease in excitatory synaptic transmission, which is likely due to an increase in inhibitory transmission, and these mechanisms could not account for the previously observed increase in synaptic transmission and pyramidal cell firing (Haas & Gahwiler, 1992). To understand the role of hippocampal GABAergic interneurones in VIP-mediated facilitation of synaptic transmission, we have now evaluated how pre- and postsynaptic modulation of GABAergic transmission (to both pyramidal cells and interneurones) by VIP could influence synaptic transmission to CA1 pyramidal neurones. A preliminary account of some of the results already appeared (Cunha-Reis et al., 2002b).