Plasticity in Fast Synaptic Inhibition of Adult Oxytocin Neurons Caused by Switch in GABAA Receptor Subunit Expression

Abstract

We found that magnocellular oxytocin neurons in adult female rats exhibit an endogenous GABA(A) receptor subunit switch around parturition: a decrease in alpha1:alpha2 subunit mRNA ratio correlated with a decrease in allopregnanolone potentiation and increase in decay time constant of the GABA(A) receptor-mediated IPSCs in these cells. The causal relationship between changes in alpha1:alpha2 mRNA ratio and the ion channel kinetics was confirmed using in vitro antisense deletion. Further, GABA(A) receptors exhibited a tonic inhibitory influence upon oxytocin release in vivo, and allopregnanolone helped to restrain oxytocin neuron in vitro firing only before parturition, when the alpha1:alpha2 subunit mRNA ratio was still high. Such observations provide evidence for the physiological significance of GABA(A) receptor subunit heterogeneity and plasticity in the adult brain.

Effect of Adrenalectomy on Miniature Inhibitory Postsynaptic Currents in the Paraventricular Nucleus of the Hypothalamus

“…While mIPSCs in magnocellular neurons displayed a high-frequency, large peak amplitude and fast decay, parvocellular neuron mIPSCs were low in frequency, had a small peak amplitude, and were more slowly decaying. The mIPSC characteristics for magnocellular neurons as found in this study closely resemble those described for magnocellular neurons in the SON (Brussaard et al 1997). The higher frequency of mIPSCs in magnocellular neurons may be related to the fact that the percentage of inhibitory synapses making contact with the soma is higher in the magnocellular than the parvocellular region, as established with electronmicroscopy (Decavel and Van den Pol 1990).…”

“…These criteria are based on earlier studies, describing mIPSC properties in other hypothalamic nuclei or other brain areas (Brussaard et al 1997;Wierenga and Wadman 1999). Based on these criteria about 14% of all initially mIPSC detected events were discarded, equally distributed over the different treatment groups.…”

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

“…Brussaard and colleagues (1997) have shown that that high concentrations of allopregnanolone (1 -10 μM) prolong sIPSC decay and diminish action potential firing in magnocellular neurons from the SON of juvenile female rats and that this modulation also depends upon a G protein/ PKC-dependent mechanism. Remarkably, in contrast to juvenile females, the potentiating effect of allopregnanolone on GABAergic sIPSCs and its inhibitory effect on action potential firing were found to be absent or markedly reduced in parturient or postpartum females (Brussaard et al, 1997). The change in allopregnanolone at the time of parturition was attributed to enhanced PKC activation and phosphorylation of postsynaptic GABA A receptors arising from oxytocin receptor-mediated signaling .…”

“…Using this methodology, allopregnanolone concentrations in cortical homogenates were estimated to be ~1-2 ng/g in juvenile, ~1 ng/g in diestrous, 4-6 ng/g in estrous, and 4-8 ng/g in proestrous females, with levels reaching ~10-30 ng/g during pregnancy (Paul and Purdy, 1992;Corpéchot et al, 1993;Concas et al, 1998;Kellogg and Frye, 1999). These assessments have been used to estimate that allopregnanolone levels are diestrus females (Paul and Purdy, 1992), but can reach ~100 nM during the late stages of pregnancy (see for example; Brussaard et al, 1997;Lambert et al, 2003). The androgenic neurosteroid, 3α-diol, also showed cycle-dependent variation in cortical homogenates, with levels being lowest in diestrus I (0.08 ng/g) and rising steadily as the cycle progresses to a maximum of 0.33 ng/g during estrus (Kellogg and Frye, 1999).…”

“…Initial reports indicated that a shift in the relative expression levels of GABA A receptor α 1 and α 2 subunit mRNAs in these neurons as female rodents transit from late pregnancy through parturition and to a lactating state results in a concomitant decrease in the sensitivity of these neurons to modulation by allopregnanolone, thus promoting disinhibition and enhanced firing of oxytocin neurons (Fénelon and Herbison, 1996a;Brussaard et al, 1997;Brussaard et al, 1999; for review Brussaard and Herbison, 2000;Herbison, 2001). While effects of antisense knockdown of α 2 subunit expression in neocortical slices demonstrated the expected acceleration of synaptic current decay kinetics (Brussaard et al, 1997), SON slices were not tested with anti-sense constructs, nor were antisense-treated cortical slices assayed for differences in the sensitivity to allosteric modulation by allopregnanolone to test directly if changes in α subunit expression resulted in concomitant changes in allopregnanolone potentiation. More recently, assessment of allopregnanolone sensitivity in α 1 -/-mice indicates that the absence of the α 1 subunit does not alter the efficacy of allopregnanolone modulation (Koksma et al, 2003); a result consistent with a number of studies from recombinant GABA A receptors and native receptors in other brain regions indicating that α 1 vs. α 2 subunit composition has only a modest correlation with allosteric modulation of recombinant GABA A receptors elicited by the positive neurosteroids and no correlation with allopregnanolone modulation in primary neurons (Section 3.2).…”