Taurine Recovery of Learning Deficits Induced by Developmental Pb²⁺ Exposure

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 I_ca²⁺ through NMDA_Rs 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 GABA_AR mediated inhibition, thereby attenuating improper brain excitability. Mechanistically, taurine is developmentally a potent neuromodulator that acts as a GABA_AR agonist and more recently has been reported as a partial agonist for NMDA_Rs 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 GABA_BR agonist, dose dependently showed no interaction with Pb²⁺ effects on ASR-PPI learning. Thus, taurine may work as an important neuromodulator at both GABA_ARs and NMDA_Rs 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 GABA_AR dependent inhibitory learning is altered by early Pb²⁺ exposure and taurine was able to recover these Pb²⁺ induced deficits through neuromodulation of GABA_ARs and potentially NMDA_Rs 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.