Chapter 11 - Imbalance in glutamatergic and GABAergic transmission in Down syndrome and therapeutic targets

Abstract

The cognitive feature of Down syndrome (DS) has been ascribed with reduced number and density of neurons in diverse regions of brain, prominently in the cortex, hippocampus, and cerebellum, with a gestational onset to aggravation at adulthood. The basic wiring of the human nervous system is configured during early development, when the key events (birth and migration of neurons, synapse formation, and maturation) occur with refinement of circuit connections of functional neural circuits with balanced excitatory (glutamatergic)/inhibitory (GABAergic) (E/I) components. Seemingly, the aberrant neurotransmission perturbs the synaptic plasticity through alteration of E/I balance, which finally impairs learning and memory in DS. The γ-amino-butyric acid (GABA) is produced by the GABAergic neurons in the mammalian brain during the formation of GABAergic synapses and acts as the major inhibitory neurotransmitter. GABA binds to GABA-receptors (GABA-A and GABA-B), opens a chloride channel, and reduces neuronal excitability in the central nervous system (CNS). The strength of GABAergic synapses is regulated by glutamatergic transmission. Moreover, GABA signaling, in most immature CNS regions, is established before glutamatergic transmission, indicating that GABA is the primary excitatory transmitter during early development of brain. DS-related GABAergic and glutamatergic neurotransmission have been assessed mostly in DS mouse models. Indeed, cooperation of depolarizing GABA-A signaling and glutamatergic excitatory alterations appeared to be brain-region specific in trisomic Ts65Dn mice. The present chapter has clearly emphasized the multifaceted consequences of neurotransmission in DS brain and modulation of the neurotransmission with targeted antagonists of GABA-inhibition in trisomic mice and DS patients.