Amelioration of cognitive impairments induced by GABA hypofunction in the male rat prefrontal cortex by direct and indirect dopamine D agonists SKF-81297 and d-Govadine.

Deficits in prefrontal cortex (PFC) GABAergic neurotransmission are linked to cognitive impairments seen in schizophrenia and other disorders, and pharmacological reduction of PFC GABA transmission disrupts processes including working and spatial memory. This provides an opportunity to examine whether compounds capable of neutralizing GABAergic dysfunction may ameliorate these cognitive deficits. PFC dopamine (DA) D receptor activation enhances GABA transmission, raising the possibly that direct or indirect agonists of DA D receptors would be effective in reversing working memory and other forms of cognitive deficits.

Disinhibition of the prefrontal cortex leads to brain-wide increases in neuronal activation that are modified by spatial learning.

Deficient prefrontal cortex (PFC) GABA function is hypothesized to play a role in schizophrenia and other psychiatric disorders. In rodents, PFC GABA receptor antagonism produces cognitive and behavioral changes relevant to these disorders, including impaired spatial memory assessed with the traditional working/reference memory radial maze task. This aspect of spatial memory does not depend on PFC, suggesting that deficient PFC GABAergic transmission may interfere with non-PFC-dependent cognitive functions via aberrant increases in PFC output.

Regulation of sustained attention, false alarm responding and implementation of conditional rules by prefrontal GABA transmission: comparison with NMDA transmission.

Rationale: Both prefrontal cortex (PFC) GABA and NMDA transmission regulate attentional processes, yet how they may differentially regulate signal detection or other aspects of attention is unclear.

Objectives: We examined PFC GABA and NMDA receptor regulation of attention using a sustained attention task (SAT) permitting identification of distinct forms of impairments. As this task requires implementation of conditional rules, we also investigated how reducing PFC GABA transmission affected performance of visual and auditory conditional discriminations.

Prefrontal cortical GABAergic and NMDA glutamatergic regulation of delayed responding.

NMDA glutamatergic and GABAergic transmission have both been implicated in regulating working memory functions mediated by the prefrontal cortex (PFC), and perturbations in these neurotransmitter systems have been proposed to underlie deficits in these functions observed in schizophrenia. Here, we examined the consequence of disrupting GABAergic or NMDA glutamatergic transmission within the medial PFC of rats on a delayed-response paradigm with translational relevance to working memory tasks used with humans. The operant delayed non-match to position task consisted of a sample phase (one lever extended) and a choice phase wherein rats were required to choose the opposite lever, separated by a variable delay (1-24 s).

Prefrontal cortical GABA modulation of spatial reference and working memory.

Background: Dysfunction in prefrontal cortex (PFC) GABA transmission has been proposed to contribute to cognitive dysfunction in schizophrenia, yet how this system regulates different cognitive and mnemonic functions remains unclear.

Methods: We assessed the effects of pharmacological reduction of GABAA signaling in the medial PFC of rats on spatial reference/working memory using different versions of the radial-arm maze task. We used a massed-trials procedure to probe how PFC GABA regulates susceptibility to proactive interference.

unc5c haploinsufficient phenotype: striking similarities with the dcc haploinsufficiency model.

DCC and UNC5 homologs (UNC5H) are guidance cue receptors highly expressed by mesocorticolimbic dopamine neurons. We have shown that dcc heterozygous mice exhibit increased dopamine, but not norepinephrine, innervation and function in medial prefrontal cortex. Concomitantly, dcc heterozygotes show blunted mesolimbic dopamine release and behavioral responses to stimulant drugs.

Toll-like receptor-4 genotype influences the survival of cystic fibrosis mice.

Toll-like receptor (Tlr) 4 is a lipopolysaccharide (LPS) receptor that contributes to the regulation of intestinal cell homeostasis, a condition that is altered in the intestines of cystic fibrosis mice. Herein, we assessed whether Tlr4 genotype influences cystic fibrosis intestinal disease by producing and phenotyping 12-wk (adult)- and 4-day (neonate)-old mice derived from BALB cystic fibrosis transmembrane conductance regulator, Cftr(+/tm1Unc) and C.C3-Tlr4(Lps-d)/J (Tlr4(-/-)), progenitors.