No abstract

1 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. 2 VIP (0.1-100 nM) increased [ 3 H]GABA release from hippocampal synaptosomes (maximum effect at 1 nM VIP; 63.874.0%) but did not change [ 3 H]glutamate release. 3 VIP (0.3-30 nM) enhanced synaptic transmission in hippocampal slices (maximum effect at 1 nM VIP; field excitatory postsynaptic potentials (epsp) slope: 23.771.1%; population spike amplitude: 20.371.7%). The action on field epsp slope was fully dependent on GABAergic transmission since it was absent in the presence of picrotoxin (50 mM) plus CGP55845 (1 mM). 4 VIP (1 nM) did not change paired-pulse facilitation but increased paired-pulse inhibition in CA1 pyramidal cells (16.070.9%), reinforcing the involvement of GABAergic transmission in the action of VIP. 5 VIP (1 nM) increased muscimol-evoked inhibitory currents by 36.478.7% 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. 6 In conclusion, concerted pre-and postsynaptic actions of VIP lead to disinhibition of pyramidal cell dendrites causing an enhancement of synaptic transmission.

Long‐term potentiation (LTP) is a highly studied cellular process, yet determining the transduction and gamma aminobutyric acid (GABAergic) pathways that are the essential versus modulatory for LTP elicited by theta burst stimulation (TBS) in the hippocampal Cornu Ammonis 1 (CA1) area is still elusive, due to the use of different TBS intensities, patterns or different rodent/cellular models. We now characterised the developmental maturation and the transduction and GABAergic pathways required for mild TBS‐induced LTP in hippocampal CA1 area in male rats. LTP induced by TBS (5x4) (five bursts of four pulses delivered at 100 Hz) lasted for up to 3 h and was increasingly larger from weaning to adulthood. Stronger TBS patterns ‐ TBS (15x4) or three TBS (15x4) separated by 6 min induced nearly maximal LTP not being the best choice to study the value of LTP‐enhancing drugs. LTP induced by TBS (5x4) in young adults was fully dependent on N‐methyl D‐aspartate (NMDA) receptor and calmodulin‐dependent protein kinase II (CaMKII) activity but independent of protein kinase A (PKA) or protein kinase C (PKC) activity. Furthermore, it was partially dependent on GABAB receptor activation and was potentiated by GABAA receptor blockade and less by GAT‐1 transporter blockade. AMPA GluA1 phosphorylation on Ser831 (CaMKII target) but not GluA1 Ser845 (PKA target) was essential for LTP expression. The phosphorylation of the Kv4.2 channel was observed at Ser438 (CaMKII target) but not at Thr602 or Thr607 (ERK/MAPK pathway target). This suggests that cellular kinases like PKA, PKC, or kinases of the ERK/MAPK family although important modulators of TBS (5x4)‐induced LTP may not be essential for its expression in the CA1 area of the hippocampus.

Vasoactive intestinal peptide (VIP) is an important modulatory peptide throughout the CNS acting as a neurotransmitter, neurotrophic or neuroprotective factor. In the hippocampus, a brain area implicated in learning and memory processes, VIP has a crucial role in the control of GABAergic transmission and pyramidal cell activity in response to specific network activity by either VIP-containing basket cells or interneuron-selective (IS) interneurons and this appears to have a differential impact in hippocampal-dependent cognition. At the cellular level, VIP regulates synaptic transmission by either promoting disinhibition, through activation of VPAC1 receptors, or enhancing pyramidal cell excitability, through activation of VPAC2 receptors. These actions also control several important synaptic plasticity phenomena such as long-term potentiation (LTP) and long-term depression (LTD). This paper reviews the current knowledge on the activation and multiple functions of VIP expressing cells in the hippocampus and their role in controlling synaptic transmission, synaptic plasticity and learning and memory processes, discussing also the role of VPAC1 and VPAC2 VIP receptors in the regulation of these different processes. Furthermore, we address the current knowledge regarding changes in VIP mediated neurotransmission in epileptogenesis and mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), and discuss the therapeutic opportunities of using selective VIP receptor ligands to prevent epileptogenesis and cognitive decline in MTLE-HS.