Differential Patterns of Subcortical Activity Evoked by Glial GLT-1 Blockade in Prelimbic and Infralimbic Cortex: Relationship to Antidepressant-Like Effects in Rats

Advance Access Publication: August Differential Patterns of Subcortical Activity Evoked by Glial GLT-1 Blockade in Prelimbic and Infralimbic Cortex: Relationship to Antidepressant-Like Effects in Rats Júlia Gasull-Camós 0 Maria Luisa Soto-Montenegro 0 Marta Casquero-Veiga 0 Manuel Desco 0 Francesc Artigas 0 Anna Castañé 0 0 Department of Neurochemistry and Neuropharmacology, CSIC-Institut d'Investigacions Biomèdiques de Barcelona , Barcelona , Spain ( Drs Artigas and Castañé and Ms Gasull-Camós); Institut d'Investigacions Biomèdiques Background: Glutamatergic neurotransmission has emerged as a novel target in antidepressant drug development, with a critical role of the ventral anterior cingulate cortex. We recently reported that blockade of the astrocytic glutamate transporter GLT-1 with dihydrokainic acid in infralimbic cortex (rodent equivalent of ventral anterior cingulate cortex), but not in the adjacent prelimbic cortex, evoked robust antidepressant-like effects through α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor activation and increased serotonin release. Methods: 2-deoxy-2-[18F]-fluoro-D-glucose-positron emission tomography and computed tomography in 36 male Wistar rats microinfused bilaterally in prelimbic cortex or infralimbic cortex with dihydrokainic acid or vehicle. Results: Dihydrokainic acid microinfusion in infralimbic cortex and prelimbic cortex evoked dramatically different regional patterns of subcortical activity. In infralimbic cortex, dihydrokainic acid selectively affected midbrain areas, whereas in prelimbic cortex it affected the basal ganglia, the thalamus, and both superior and inferior colliculi. Conclusions: These results highlight the differential connectivity of infralimbic and prelimbic cortex with subcortical brain regions and support the involvement of infralimbic cortex-midbrain pathway in the antidepressant-like effects of dihydrokainic acid. infralimbic; prelimbic; glutamate transporter-1; FDG-PET; dihydrokainic acid - Significance Statement The glutamatergic system is a potential target to develop fast-acting antidepressants. On the other hand, glial cells tightly control glutamatergic synapses. We recently reported that boosting glutamatergic neurotransmission by inhibiting astrocytic glutamate uptake in a ventral area of the rat prefrontal cortex (infralimbic, IL; but not in the neighboring prelimbic cortex, PrL) evoked rapid and robust antidepressant-like effects. Using microPET scan, we show that the blockade of astrocytic glutamate uptake in IL and PrL evokes dramatically different patterns of brain activity, showing at the same time that IL-midbrain circuits (possibly involving serotonergic neurotransmission) underlie the reported antidepressant effects. Introduction The glutamatergic system is emerging as a promising venue humidity-controlled vivarium with a 12-h-light/-dark cycle for the development of fast-acting antidepressant treatments, and with food and water ad libitum (unless otherwise stated). given the immediate and persistent antidepressant effects of Experiments were performed according to the guidelines of the the noncompetitive N-methyl-D-aspartate receptor antagonist European Union Council Directive 2010/63/EU for care of laboketamine (Zarate et al., 2006) . Its unique properties appear to ratory animals and after approval by the Ethics Committee for result from the activation of α-amino-3-hydroxy-5-methyl- Animal Experimentation of Hospital Gregorio Marañón, Madrid, 4-isoxazolepropionic acid (AMPA) receptors by a metabolite Spain. (2S,6S;2R,6R)-hydroxynorketamine (Zanos et al., 2016) and by an increased synaptic plasticity evoked by mTOR signaling in rat Surgery medial prefrontal cortex (mPFC) (Li et al., 2010). Ventral regions of the anterior cingulate cortex (vACC) seem to Anesthetized rats (sodium pentobarbital, 60  mg/kg i.p.) were play a crucial role in the pathophysiology and treatment of major placed into a stereotaxic frame. Stainless-steel 22-gauge bilatdepressive disorder. Neuroimaging studies have reported contro- eral guide cannulae (Plastics One) were implanted in the cinguversial findings on the energy metabolism of that area in major late cortex: AP +3.2; ML ±0.75; DV -2.4 (Paxinos and Watson, 2005) depressive disorder patients. A reduced activity of the subgenual as reported (Gasull-Camós et  al., 2017). The coordinates were vACC was first described (Drevets et al., 1997O;ngür et al., 1998), taken from bregma and the skull. Guide cannulae were fixed whereas further studies reported an increased activity of the adja- with 3 stainless-steel screws using dental acrylic. A dummy cancent Brodmann area 25, which was normalized after effective nula was inserted inside the guide cannula and removed and treatment (Seminowicz et al., 2004M;ayberg et al., 2005) . Likewise, reinserted daily to prevent occlusion. After surgery, rats were optogenetic stimulation of the infralimbic cortex (IL, rodent equiv- all (...truncated)