Mesencephalic GABA neuronal development: no more on the other side of oblivion.

Abstract : Midbrain GABA neurons, endowed with multiple morphological, physiological and molecular character-istics as well as projection patterns are key players inter-acting with diverse regions of the brain and capable of modulating several aspects of behavior. The diversity of these GABA neuronal populations based on their location and function in the dorsal, medial or ventral midbrain has challenged efforts to rapidly uncover their developmental regulation. Here we review recent developments that are beginning to illuminate transcriptional control of GABA neurons in the embryonic midbrain (mesencephalon) and discuss its implications for understanding and treatment of neurological and psychiatric illnesses. Keywords: brain; development; GABA. DOI 10.1515/bmc-2014-0023 Received July 21 , 2014 ; accepted September 22 , 2014 Introduction The midbrain – an important relay center for sensory inputs and motor outputs networking with the forebrain, hindbrain and spinal cord – is a hub of constant activity (1 – 10) . Gamma-aminobutyric acid (GABA) neurons are key players in midbrain neuronal circuitry, robustly network-ing with glutamatergic and dopaminergic (DA) neurons to shape multiple aspects of behavior. Midbrain GABA neurons function not only as local inhibitory interneu-rons but also as projection neurons with targets in various brain regions. Along their developmental path, midbrain GABA neurons acquire molecular and functional diversity and can be divided into three categories based on anatomy and function: (1) dorsally located GABA neurons in the superior colliculus (SC) and inferior colliculus (IC); (2) medially located GABA neurons in the midbrain reticular formation (MRF) and periaqueductal gray (PAG); (3) ven-trally located GABA neurons in substantia nigra (SN), ventral tegmental area (VTA) and retrorubral field (RRF), ( Fgue1 Air ). The functional diversity of midbrain GABA neurons based on their location is fascinating. Dorsal midbrain GABA neurons together with glutamatergic neurons are involved in processing and incorporation of sensorimotor, visual, auditory, and defensive behavior (11– 16) . Although GABA neurons are present in all of the seven layered SC, an abundance of GABA neurons is found in the super-ficial layers when compared to deep and intermediate layers (17 – 20) . The SC is noteworthy for its high GABA content next only to the SN, globus pallidus and hypo-thalamus in the central nervous system (CNS) (21, 22) . Medial midbrain GABA neurons of PAG regulate vocaliza-tion, endogenous control of pain sensation, fear, anxiety and aggression (23 – 25) while those in the MRF have been implicated with sleep-wake state control (26, 27) . Ventral midbrain GABA neurons regulate DA neuron activity in the SN and VTA (6, 7, 28 – 31) and have projection targets similar to DA neurons, to the prefrontal cortex, basal ganglia and other limbic areas (6– 10) . Additionally, a con-siderable number of ascending projections from midbrain dopaminergic nuclei are GABAergic in nature (7) . Ventral midbrain GABA neurons are thus critical for the function of dopaminergic pathways; have important functional roles in control of voluntary movements, emotion, mood, motivation, processing of appetite and aversive stimuli, addiction and reward behaviors (6, 29, 32 – 35) and may be involved in the etiology of several neurological and psychiatric disorders including schizophrenia, depres-sion, mood disorders, addiction and Parkinson ’ s disease. Midbrain GABA neurons can therefore serve as important targets for treatment of neuropsychiatric disorders and for drugs of abuse. Recent evidence reveals that midbrain SN and VTA DA neurons co-release GABA although they do not synthesize it, by using GABA reuptake transporters