Abstract
Lead (Pb2+) is a historically well-documented environmental neurotoxin that produces developmental cognitive learning and memory impairments. These early neurodevelopmental impairments cause increased brain excitability via disruption of Ca2+ mediated signaling during critical periods of synaptogenesis inducing competition with Ica 2+ through NMDARs resulting in altered brain development and functioning across the lifespan. Interestingly, Pb2+ has been shown to decrease GABA transport and uptake, decrease spontaneous and depolarization-evoked GABA neurotransmission and lower the expression of glutamic acid decarboxylase (GAD); thereby, limiting excitatory GABAergic influences that regulate early developmental brain excitability and reducing inhibition across mature GABAergic networks. Taurine has been shown to regulate brain excitability in the mature brain through GABAAR mediated inhibition, thereby attenuating improper brain excitability. Mechanistically, taurine is developmentally a potent neuromodulator that acts as a GABAAR agonist and more recently has been reported as a partial agonist for NMDARs through glycine sites. We investigated the effects of developmental Pb2+ exposure on the rat’s mature inhibitory cognitive control abilities pharmacologically through anxiety and emotional learning-related behaviors and whether taurine could recover Pb2+ induced neurodevelopmental behavioral deficits later in life. Results showed that Pb2+ increased anxiety symptoms in the open field and hole board test, increased sensitivity to context fear training with cognitive deficits in both acquisition and extinction learning while producing learning deficits and inabilities in acquiring inhibitory learned associations through the acoustic startle response and pre-pulse inhibition (ASR-PPI) test. Interestingly, taurine recovered Pb2+ developmentally induced behavioral deficits in the open field and hole board test evidenced by decreased freezing and increased exploration behaviors and facilitated inhibitory dependent ASR-PPI learning to levels higher than controls. In contrast, Baclofen, a GABABR agonist, dose dependently showed no interaction with Pb2+ effects on ASR-PPI learning. Thus, taurine may work as an important neuromodulator at both GABAARs and NMDARs glycine sites, thereby increasing inhibition, enhancing Ca2+-mediated signaling, and decreasing the altered brain excitability, which impedes learning and memory from early Pb2+ exposure. Taken together our data suggests that GABAAR dependent inhibitory learning is altered by early Pb2+ exposure and taurine was able to recover these Pb2+ induced deficits through neuromodulation of GABAARs and potentially NMDARs later in life. These findings may pave the way for further exploration of taurine as a pharmacotherapy for neurodevelopmental lead poisoning in both animal and clinical models.
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Abbreviations
- ACF:
-
Auditory context cued fear conditioning
- ASR:
-
Acoustic startle response
- CFC:
-
Context fear test
- HB:
-
Hole board test
- OF:
-
Open field
- Pb2+ :
-
Lead
- PPI:
-
Pre-pulse inhibition
- Tau:
-
Taurine
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Acknowledgements
We thank Ehab Jawad for his assistance with the behavioral testing. This work was supported by CSTEP and LSAMP support along with NSF/AGEP grant # 0450360 awarded to L.S. Neuwirth. This work was also supported by travel awards to L.S. Neuwirth from SUNY-OW and NYS-UUP.
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Neuwirth, L.S. et al. (2017). Taurine Recovery of Learning Deficits Induced by Developmental Pb2+ Exposure. In: Lee, DH., Schaffer, S.W., Park, E., Kim, H.W. (eds) Taurine 10. Advances in Experimental Medicine and Biology, vol 975. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-1079-2_4
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