Research reportKainate-activated currents in the ventral tegmental area of neonatal rats are modulated by interleukin-2
Introduction
Interleukin (IL)-2 is a 15–20 kDa glycoprotein that modulates central nervous system (CNS) activity [9]. IL-2 is present and modulates activity in the mesolimbic and mesostriatal systems. IL-2 mRNA and receptors are expressed in the cortex, mesencephalon, and striatum [9], [19]. Furthermore, there is a functional relationship between IL-2 and dopamine activity in these regions. For example, IL-2 influences dopamine turnover in the medial prefrontal cortex [35] and dopamine release in the nucleus accumbens in vivo [2], [14], [24]. IL-2 also modulates K+-, veratrine-, NMDA-, and kainate-induced dopamine release from mesencephalic and basal forebrain slices in developing and adult rats [1], [15], [20]. We also showed that IL-2 modulates NMDA-activated current in dopaminergic neurons of neonatal rats [31]. Typically, IL-2-induced alterations of transmitter release occur in a biphasic manner such that opposite effects are induced by low and high doses. Additionally, IL-2 influences behavioral responses that are associated with mesolimbic and striatal dopamine activity [14], [18], [20], [25], [33], [34], [36].
In addition to modulating neurochemical activity in the mesolimbic and striatal systems, IL-2 promotes the survival of neonatal cortical, striatal, and hippocampal cells [3], [22], suggesting that it may be required for normal cell development in these areas. In support of this suggestion, IL-2 knockout mice display marked hippocampal abnormalities and cognitive deficits [21]. Further to the point, IL-2 is implicated in the etiology and pathogenesis of neurodevelopmental disorders (e.g., schizophrenia, autism) that are associated with aberrations in limbic and cortical structures. The mechanisms mediating these effects of IL-2, however, are not known.
The ventral tegmental area (VTA) is the site of origin of the mesolimbic system, a system involved in aspects of motivation, cognition, and the rewarding properties of drugs of abuse like ethanol [8], [30]. The VTA contains dopaminergic and non-dopaminergic neurons [11], [13]. The majority of cell bodies in this region are dopaminergic, the axon terminals of which release dopamine in target areas, notably the nucleus accumbens and prefrontal cortex [29]. Cell bodies in the VTA receive a monosynaptic innervation from prefrontal cortex and have N-methyl-d-aspartate (NMDA) and non-NMDA receptors [26], and glutamatergic afferents from the hippocampus to the nucleus accumbens strongly excite VTA dopamine neurons [7].
In addition to NMDA receptor/channel activity, kainate receptor/channel regulates the excitability as well the firing pattern of VTA dopamine neurons and dopamine release [12], [17], [26], [28], [29]. Kainate (KA) receptors are a family of ionotropic glutamate receptors, which mediate the excitatory synaptic transmission in various areas of the mammalian CNS. A recent study on the expression pattern of the genes encoding for KA receptor subunits indicated that most of the transcripts for KA subunits change with development and may contribute to the establishment of the fine tuning of the excitatory circuits reciprocally established between CNS areas [16].
Inasmuch as the kainate receptor/channel plays an essential role in modulating neuronal excitability of developing mesolimbic neurons, coupled with the mentioned links between IL-2 and the mesolimbic system and related pathologies, we hypothesized that IL-2 modulates the excitability of VTA neurons, and that this modulation involves interactions with the kainate receptor/channel. Using the whole-cell patch-clamp technique, we demonstrate for the first time that IL-2 potently modulates the kainate receptor/channel of developing mesolimbic neurons.
Section snippets
Isolation of neurons and electrophysiological recording
The care and use of animals and the experimental protocol of this study were approved by the Institutional Animal Care and Use Committee of University of Medicine and Dentistry of New Jersey. We performed our experiments on VTA neurons prepared as described earlier [31]. Briefly, 5- to 14-day-old Sprague–Dawley rats were decapitated. The brain was quickly excised, placed into ice-cold saline saturated with 95% O2 and 5% CO2, glued to the chilled stage of a vibratome (Campden Instruments, UK),
IL-2 potently depressed IKA in neurons freshly isolated from the VTA of neonatal rats
The vast majority of neurons tested responded to kainate (n = 35). At a negative holding potential, kainate stimulated an inward current. IL-2 (0.1–10 ng/ml) alone had no detectable effect on membrane current. Nonetheless, IL-2 regulated IKA when co-applied with kainate (Fig. 1A). The mean whole-cell peak inward current of VTA neurons elicited by application of 50 μM kainate was typically 650 ± 100 pA (n = 10). When applied extracellularly, IL-2 (0.1–10 ng/ml) depressed IKA in a
Discussion
This is the first demonstration that IL-2 potently modulates kainate receptors in the mesolimbic dopamine system. At physiologically relevant concentrations (0.1–10 ng/ml), IL-2 profoundly inhibited IKA. The present results extend our demonstration that IL-2 interacts with the NMDA receptor of neurons freshly isolated from VTA [31] and supports our contention that IL-2 interacts with excitatory amino acids in the mesolimbic system. The effects of high doses of IL-2 on IKA remain to be
Acknowledgments
Supported by grants from the NIAAA (AA-11989, AT001182, JHY), the National Alliance for Autism Research (NAAR, SZ) and the Foundation of UMDNJ (SZ). We thank Dr. Hong-Lin Niu for her assistance.
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