Developmental exposure to PCBs alters the activation of the auditory cortex in response to GABA A antagonism

Abstract

Developmental exposure of rats to polychlorinated biphenyls (PCBs) causes impairments in hearing and in the functioning of peripheral and central auditory structures. Additionally, recent work from our laboratory has demonstrated an increase in audiogenic seizures. The current study aimed to further characterize the effects of PCBs on auditory brain structures by investigating whether developmental exposure altered the magnitude of activation in the auditory cortex (AC) in response to electrical stimulation of thalamocortical afferents. Long-Evans female rats were fed cookies containing either 0 or 6 mg/kg of an environmental PCB mixture daily from 4 weeks prior to breeding until postnatal day 21. Brain slices containing projections from the thalamus to the AC were collected from adult female offspring and were bathed in artificial cerebrospinal fluid (aCSF) alone, aCSF containing a gamma-aminobutyric acid (GABA) receptor antagonist (200 nM SR95531), and aCSF containing an and N-methyl-D-aspartate (NMDA) receptor antagonist (50μM AP5). During each of these drug conditions, electrical stimulations ranging from 25-600 μA were delivered to the thalamocortical afferents. Activation of the AC was measured using flavoprotein autofluorescence imaging. Although there were no differences seen between treatment groups in the aCSF condition, there were significant increases in the ratio of aCSF/SR95531 activation in slices from PCB-exposed animals compared to control animals. This effect was seen in both the upper and lower layers of the AC. No differences in activation were noted between treatment groups when slices were exposed to AP5. These data suggest that developmental PCB exposure leads to increased sensitivity to antagonism of GABAA receptors in the AC without a change in NMDA-mediated intrinsic excitability.

Developmental PCB Exposure Disrupts Synaptic Transmission and Connectivity in the Rat Auditory Cortex, Independent of Its Effects on Peripheral Hearing Threshold

“…Vesicle release can be modified by a variety of changes, including changes of activity, membrane potential, intracellular calcium dynamics, and the readily releasable pool. Increases of spontaneous inhibition following developmental PCB exposure are consistent with previous findings that thalamocortical transmission is more strongly enhanced by GABA A -receptor blockade in PCB-exposed subjects ( Sadowski et al, 2016 ). Because PCB exposure increases spontaneous inhibitory input to auditory cortical neurons, release from inhibition with GABA A -receptor antagonist application is more pronounced in PCB-exposed subjects compared with controls.…”

“…Complex auditory behaviors such as precise sound localization ( Lomber and Malhotra, 2007 ), temporal processing ( Threlkeld et al, 2008 ), and frequency discrimination of complex stimuli ( Znamenskiy and Zador, 2013 ) require auditory cortical processing in mammals. Developmental exposure to PCBs alters the physiology of the auditory cortex, including delayed auditory P300 latencies ( Vreugdenhil et al, 2004 ), disrupted tonotopic organization of receptive fields ( Kenet et al, 2007 ), and increased sensitivity to GABA blockade ( Sadowski et al, 2016 ). However, the synaptic mechanisms underlying these changes are not known.…”

“…Consistent with these predictions, PCB exposure reduces expression of GAD65 in the inferior colliculus ( Bandara et al, 2016 ). However, in the cortex, GAD65 levels are unaffected and thalamocortical transmission is more vulnerable to GABA antagonism in PCB-exposed rats, suggesting PCB treatment is associated with paradoxically higher background levels of cortical inhibition ( Bandara et al, 2016 ; Sadowski et al, 2016 ).…”

Developmental PCB exposure disrupts synaptic transmission and connectivity in the rat auditory cortex, independent of its effects on peripheral hearing threshold

“…Vesicle release can be modified by a variety of changes, including changes of activity, membrane potential, intracellular calcium dynamics, and the readily releasable pool. Increases of spontaneous inhibition following developmental PCB exposure are consistent with previous findings that thalamocortical transmission is more strongly enhanced by GABAA-receptor blockade in PCB-exposed subjects (Sadowski et al, 2016). Because PCB exposure increases spontaneous inhibitory input to auditory cortical neurons, release from inhibition with GABAAreceptor antagonist application is more pronounced in PCB-exposed subjects compared to controls.…”

“…Complex auditory behaviors such as precise sound localization (Lomber and Malhotra, 2007), temporal processing (Threlkeld et al, 2008), and frequency discrimination of complex stimuli (Znamenskiy and Zador, 2013) require auditory cortical processing in mammals. Developmental exposure to PCBs alters the physiology of the auditory cortex, including delayed auditory P300 latencies (Vreugdenhil et al, 2004), disrupted tonotopic organization of receptive fields (Kenet et al, 2007), and increased sensitivity to GABA blockade (Sadowski et al, 2016). However, the synaptic mechanisms underlying these changes are not known.…”