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The Journal of Neuroscience, September 14, 2005, 25(37):8468-8481; doi:10.1523/JNEUROSCI.2271-05.2005

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Behavioral/Systems/Cognitive
Genetic Enhancement of Visual Learning by Activation of Protein Kinase C Pathways in Small Groups of Rat Cortical Neurons

Guo-rong Zhang,¹ Xiaodan Wang,¹ Lingxin Kong,¹ Xiu-gui Lu,¹ Brian Lee,¹ Meng Liu,¹ Mei Sun,¹ Corinna Franklin,¹ Robert G. Cook,² and Alfred I. Geller¹

¹Department of Neurology, West Roxbury Veterans Affairs Hospital/Harvard Medical School, West Roxbury, Massachusetts 02132, and ²Department of Psychology, Tufts University, Medford, Massachusetts 02155

Although learning and memory theories hypothesize that memories are encoded by specific circuits, it has proven difficult to localize learning within a cortical area. Neural network theories predict that activation of a small fraction of the neurons in a circuit can activate that circuit. Consequently, altering the physiology of a small group of neurons might potentiate a specific circuit and enhance learning, thereby localizing learning to that circuit. In this study, we activated protein kinase C (PKC) pathways in small groups of neurons in rat postrhinal (POR) cortex. We microinjected helper virus-free herpes simplex virus vectors that expressed a constitutively active PKC into POR cortex. This PKC was expressed predominantly in glutamatergic and GABAergic neurons in POR cortex. This intervention increased phosphorylation of five PKC substrates that play critical roles in neurotransmitter release (GAP-43 and dynamin) or glutamatergic neurotransmission (specific subunits of AMPA or NMDA receptors and myristoylated alanine-rich C kinase substrate). Additionally, activation of PKC pathways in cultured cortical neurons supported activation-dependent increases in release of glutamate and GABA. This intervention enhanced the learning rate and accuracy of visual object discriminations. In individual rats, the numbers of transfected neurons positively correlated with this learning. During learning, neuronal activity was increased in neurons proximal to the transfected neurons. These results demonstrate that potentiating small groups of glutamatergic and GABAergic neurons in POR cortex enhances visual object learning. More generally, these results suggest that learning can be mediated by specific cortical circuits.

Key words: visual learning; postrhinal cortex; protein kinase C; neurotransmitter release; glutamate receptor; herpes simplex virus vector

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Received April 11, 2005; revised July 10, 2005; accepted July 11, 2005.

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