Brain Research 885 2000 14–24 www.elsevier.com locate bres
Research report
Interferon-a inhibits long-term potentiation and unmasks a long-term depression in the rat hippocampus
´ ´
Victor Mendoza-Fernandez, R. David Andrew, Carlos Barajas-Lopez
Department of Anatomy and Cell Biology , Botterell Hall, Ninth Floor, Queen’s University, Kingston, Ontario K7L 3N6, Canada
Accepted 15 August 2000
Abstract
Interferons IFN appear to have various neuromodulatory actions. Here, we characterized the actions of IFN-a on the electro- physiological properties of CA1 hippocampal neurons using intracellular recordings. Superfusion of this cytokine did not alter the resting
membrane potential, cell input resistance, action potentials, nor GABA-mediated fast synaptic potentials. IFN-a inhibited glutamate- mediated excitatory postsynaptic potentials gEPSPs and reversed or prevented long-term potentiation LTP induced by high-frequency
tetanic stimulation. IFN-a reduced gEPSP amplitude far below its control value. Only a short-term potentiation STP was observed when either IFN-a or
D
-2-amino-5-phosphonovalerato APV; NMDA receptor antagonist were present during tetanic stimulation. After this STP in presence of APV, IFN-a had no effect on gEPSPs. APV had no effect on LTP when applied after tetanic stimulation and did also
not prevent IFN-a effect on LTP. Genistein a tyrosine kinase inhibitor or heat inactivation prevented IFN-a effects. IFN-a also decreased the depolarization induced by local application of glutamate but did not modify those induced by NMDA. Similarly, IFN-a
reversed the potentiation induced by tetanic stimulation of glutamate-induced depolarizations. IFN-a did not affect long-term depression LTD induced by low-frequency tetanic stimulation. In conclusion, IFN-a-induced inhibition of LTP is, at least in part, mediated by a
postsynaptic effect, by tyrosine kinase activity, and by non-NMDA glutamate receptors. Inhibition of LTP by IFN-a unmasks LTD which is induced by the same high-frequency tetanic stimulation.
2000 Elsevier Science B.V. All rights reserved.
Theme : Excitable membranes and synaptic transmission
Topic : Long-term potentiation: pharmacology
Keywords : Long-term potentiation; Long-term depression; Interferon-a; Hippocampus; Electrophysiology; Synapse
1. Introduction nervous systems indicating a neuromodulatory role for
these cytokines [2,5,20]. Interferons are well-known immunomodulators that are
The effects of interferon-a IFN-a on the hippocampal ´
released from various types of cells during viral infections. electrical activity was first reported by Prieto-Gomez et al.
In the brain, these and other cytokines can be synthesized [21], who found that the microiontophoretic application of
and released by glial and neuronal cells [18,19,22]. In IFN-a produced an increase of the action potential fre-
addition, various neurological side effects are common quency in dorsal hippocampal neurons. This suggests the
during IFN-a therapy including: fever, anorexia, fatigue, hypothesis that IFN-a modulates the excitability of hip-
behavioral changes, alteration of sleep patterns, mood pocampal neurons. Later D’Arcangelo et al. [4] found that
alterations, and impaired learning and memory. These rat IFN-a inhibits long-term potentiation LTP in the CA1
observations suggest that these cytokines directly affect the hippocampal region and decreases, at relatively high
central nervous system [2,5,20]. In agreement, interferons concentrations, basal synaptic transmission.
affect specific neuronal properties in peripheral and central LTP and long-term depression LTD are two well-
known experimental models of neural plasticity in the CNS which are thought to play a role in memory [11–13]. The
Corresponding author. Tel.: 11-613-533-2861; fax: 11-613-533-
biochemical cascades that support these changes in synap-
2566. ´
E-mail address : barajascmeds.queensu.ca C. Barajas-Lopez.
tic strength have been recently reviewed [11,12]. It is
0006-8993 00 – see front matter
2000 Elsevier Science B.V. All rights reserved. P I I : S 0 0 0 6 - 8 9 9 3 0 0 0 2 8 7 7 - 8
V . Mendoza-Fernandez et al. Brain Research 885 2000 14 –24
15
generally accepted that activation of several kinases are was held at 2100 mV by injecting hyperpolarizing current.
essential for the development of LTP and this is seen with Cell input resistance and time constant were measured
stimuli that produce relatively high concentrations of from electrotonic potentials induced by intracellular in-
intracellular calcium. An increase in the activity of several jection of constant current pulses 2100 pA and 100 ms
protein phosphatases, on the other hand, appear to be part applied at the resting membrane potential. After the gEPSP
of the biochemical events responsible for LTD, which is amplitude was stable for 20 min, the hyperpolarizing
induced with stimuli that produce a low to moderate current was removed and either LTP or LTD was induced.
increase in the intracellular calcium concentration. A For LTP two 1-s trains of electrical pulses 100 Hz were
relatively low-frequency stimulation of the glutaminergic applied to the Schaffer collateral-commissural afferents at
fibres that innervate CA1 neurons is known to induce LTD, an interval of 10 s. After this tetanic stimulation, the
whereas their stimulation at higher frequency induces LTP. membrane potential was again current-clamped to 2100
In the present study, we characterized the effects of mV and gEPSPs recorded over the next 40–120 min. LTD
IFN-a on the electrophysiological properties of CA1 was induced by 5 Hz stimulation to the Schaffer collateral-
neurons using intracellular recordings. Our evidence indi- commissural afferents for 5 min.
cates that this cytokine inhibits specifically LTP and Unless otherwise stated, drugs were applied by superfu-
glutamate excitatory postsynaptic potentials without LTD, sion. Because IFN-a responses did not desensitize, this
membrane excitability, or synaptic potentials mediated by cytokine was applied at progressively higher concentration
GABA -receptors. to obtain the concentration–response curve. In some
A
experiments, one pipette tip diameter 3–6 mm was filled with glutamate 5 mM, pH 7.4 or NMDA 10 mM, pH
2. Materials and methods 7.4 and a few nanoliters of these solutions were pressure
