Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction

2003 ◽  
Vol 174 (1) ◽  
Author(s):  
DavidA. Lewis ◽  
DavidW. Volk ◽  
Takanori Hashimoto
Brain ◽  
2006 ◽  
Vol 129 (11) ◽  
pp. 2923-2930 ◽  
Author(s):  
D.-F. Zhu ◽  
Z.-X. Wang ◽  
D.-R. Zhang ◽  
Z.-L. Pan ◽  
S. He ◽  
...  

2008 ◽  
Vol 99 (6) ◽  
pp. 2985-2997 ◽  
Author(s):  
Kay Thurley ◽  
Walter Senn ◽  
Hans-Rudolf Lüscher

Dopaminergic modulation of prefrontal cortical activity is known to affect cognitive functions like working memory. Little consensus on the role of dopamine modulation has been achieved, however, in part because quantities directly relating to the neuronal substrate of working memory are difficult to measure. Here we show that dopamine increases the gain of the frequency-current relationship of layer 5 pyramidal neurons in vitro in response to noisy input currents. The gain increase could be attributed to a reduction of the slow afterhyperpolarization by dopamine. Dopamine also increases neuronal excitability by shifting the input-output functions to lower inputs. The modulation of these response properties is mainly mediated by D1 receptors. Integrate-and-fire neurons were fitted to the experimentally recorded input-output functions and recurrently connected in a model network. The gain increase induced by dopamine application facilitated and stabilized persistent activity in this network. The results support the hypothesis that catecholamines increase the neuronal gain and suggest that dopamine improves working memory via gain modulation.


2001 ◽  
Vol 86 (4) ◽  
pp. 2041-2053 ◽  
Author(s):  
Toshiyuki Sawaguchi ◽  
Michiyo Iba

In primates, dorsolateral areas of the prefrontal cortex (PFC) play a major role in visuospatial working memory. To examine the functional organization of the PFC for representing visuospatial working memory, we produced reversible local inactivation, with the local injection of muscimol (5 μg, 1 μl), at various sites ( n = 100) in the dorsolateral PFC of monkeys and observed the behavioral consequences in an oculomotor delayed-response task that required memory-guided saccades for locations throughout both visual fields. At 82 sites, the local injection of muscimol induced deficits in memory-guided saccades to a few specific, usually contralateral, target locations that varied with the location of the injection site. Such deficits depended on the delay length, and longer delays were associated with larger deficits in memory-guided saccades. The injection sites and affected spatial locations of the target showed a gross topographical relationship. No deficits appeared for a control task in which the subject was required to make a visually guided saccade to a visible target. These findings suggest that a specific site in the dorsolateral PFC is responsible for the working memory process for a specific visuospatial coordinate to guide goal-directed behavior. Further, memoranda for specific visuospatial coordinates appear to be represented in a topographical memory mapwithin the dorsolateral PFC to represent visuospatial working memory processes.


2021 ◽  
Vol 13 ◽  
Author(s):  
Dibyadeep Datta ◽  
Shannon N. Leslie ◽  
Elizabeth Woo ◽  
Nishita Amancharla ◽  
Ayah Elmansy ◽  
...  

Glutamate carboxypeptidase II (GCPII) expression in brain is increased by inflammation, and reduces NAAG (N-acetyl aspartyl glutamate) stimulation of mGluR3 signaling. Genetic insults in this signaling cascade are increasingly linked to cognitive disorders in humans, where increased GCPII and or decreased NAAG-mGluR3 are associated with impaired prefrontal cortical (PFC) activation and cognitive impairment. As aging is associated with increased inflammation and PFC cognitive deficits, the current study examined GCPII and mGluR3 expression in the aging rat medial PFC, and tested whether GCPII inhibition with 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) would improve working memory performance. We found that GCPII protein was expressed on astrocytes and some microglia as expected from previous studies, but was also prominently expressed on neurons, and showed increased levels with advancing age. Systemic administration of the GCPII inhibitor, 2-MPPA, improved working memory performance in young and aged rats, and also improved performance after local infusion into the medial PFC. As GCPII inhibitors are well-tolerated, they may provide an important new direction for treatment of cognitive disorders associated with aging and/or inflammation.


1996 ◽  
Vol 39 (7) ◽  
pp. 565 ◽  
Author(s):  
D.C. Javitt ◽  
A-M. Shelley ◽  
E. Leiderman ◽  
L. March ◽  
N. Cowan ◽  
...  

1997 ◽  
Vol 24 (1-2) ◽  
pp. 238
Author(s):  
Anne-Marie Shelley ◽  
Daniel C. Javitt ◽  
Herbert G. Vaughan ◽  
Gail Silipo

2000 ◽  
Vol 34 (s1) ◽  
pp. A13-A13
Author(s):  
C R Clark ◽  
A C McFarlane ◽  
P Morris ◽  
G F Egan ◽  
D L Weber ◽  
...  

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