Abstract
Kainate receptor (KAR) subunits are believed to be involved in abnormal GABAergic neurotransmission in the hippocampus (HIPP) in schizophrenia (SZ) and bipolar disorder. Postmortem studies have shown changes in the expression of the GluR5/6 subunits of KARs in the stratum oriens (SO) of sectors CA2/3, where the basolateral amygdala (BLA) sends a robust projection. Previous work using a rat model of SZ demonstrated that BLA activation leads to electrophysiological changes in fast-spiking interneurons in SO of CA2/3. The present study explores KAR modulation of interneurons in CA2/3 in response to BLA activation. Intrinsic firing properties of these interneurons through KAR-mediated activity were measured with patch-clamp recordings from rats that received 15 days of picrotoxin infusion into the BLA. Chronic BLA activation induced changes in the firing properties of CA2/3 interneurons associated with modifications in the function of KARs. Specifically, the responsiveness of these interneurons to activation of KARs was diminished in picrotoxin-treated rats, while the after-hyperpolarization (AHP) amplitude was increased. In addition, we tested blockers of KAR subunits which have been shown to have altered gene expression in SO sector CA2/3 of SZ subjects. The GluR5 antagonist UBP296 further decreased AP frequency and increased AHP amplitude in picrotoxin-treated rats. Application of the GluR6/7 antagonist NS102 suggested that activation of GluR6/7 KARs may be required to maintain the high firing rates in SO interneurons in the presence of KA. Moreover, the GluR6/7 KAR-mediated signaling may be suppressed in PICRO-treated rats. Our findings indicate that glutamatergic activity from the BLA may modulate the firing properties of CA2/3 interneurons through GluR5 and GluR6/7 KARs. These receptors are expressed in GABAergic interneurons and play a key role in the synchronization of gamma oscillations. Modulation of interneuronal activity through KARs in response to amygdala activation may lead to abnormal oscillatory rhythms reported in SZ subjects.
Highlights
Stimulated learning and memory in the hippocampus (HIPP) is mediated by glutamatergic afferents from the basolateral amygdala (BLA) [1]
This was tested by adding kainic acid (KA) to the external solution alone or together with selective blockers of the specific Kainate receptor (KAR) subunits, GluR5 and GluR6/7, which have been shown previously to have altered gene expression in stratum oriens (SO) sector CA2/3 in SZ subjects [21]
Instantaneous firing frequency (IFF) shows a strong action potentials (APs) frequency adaptation in the presence of KA in slices from PICRO-treated rats (ANOVA: p = 0.0001, n = 13, a = 8, before KA application and n = 13, a = 8, after KA application, Figure 1F). These results indicate that the responsiveness of SO interneurons to activation of the KAR signaling pathways might be modulated by the chronic increases of activity in excitatory inputs coming from the BLA to SO of CA2/3 of the HIPP
Summary
Stimulated learning and memory in the hippocampus (HIPP) is mediated by glutamatergic afferents from the basolateral amygdala (BLA) [1]. Deficits of episodic and associative memory in schizophrenia (SZ) are associated with HIPP dysfunction [3,4,5] and may be related to tonic hyperactivation of this brain region [6,7,8] This abnormal output from the HIPP may derive from a loss of GABAergic interneurons [9,10] and their regulation by the glutamatergic system [11,12,13], resulting in a failure of inhibitory activity [14,15]. We observed an increase in currents mediated by hyperpolarization-activated cationic channels (Ih) These channels are known to be involved in the regulation of the excitability of neurons, confirming previous microarray-based gene expression profiling studies showing increased expression of the hyperpolarization-activated Ih (HCN3 and 4) channels in SZs [19,20]. To explore whether KARs mediate the influence of BLA fibers on FS interneurons in SO of CA2/3, we used the rodent model of neural circuitry abnormalities in SZ to examine the cellular mechanisms through which KARs, alone and in combination with hyperpolarizationactivated (Ih) channels, may influence the firing rates and other electrical properties of HIPP GABA cells
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