Learning-related intrinsic excitability changes of pyramidal neurons via modulation of the postburst afterhyperpolarization (AHP) have been repeatedly demonstrated in multiple brain regions (especially the hippocampus), after a variety of learning tasks, and in multiple species. While exciting and important, the changes in pyramidal neurons are only a part of the neural circuitry involved in successful learning. For a more complete picture of the dynamic learning-related changes in the neural network, changes in inhibitory circuitry must also be systematically examined and characterized. Here we show in young adult rats and mice that learning the hippocampus-dependent trace eyeblink conditioning task induces enhanced inhibition onto CA1 pyramidal neurons mediated, in part, by an increase in intrinsic excitability of somatostatin-positive inhibitory neurons (SOMs). Furthermore, both CA1 pyramidal and SOM interneurons shared a common cellular mechanism (reduction in SK channel mediated AHP) that led to the learning-induced increased intrinsic excitability.

McKay BM, Matthews EA, Oliveira FA, Disterhoft JF. Intrinsic neuronal excitability is reversibly altered by a single experience in fear conditioning. J Neurophysiol 102: 2763-2770. First published September 2, 2009 doi:10.1152/jn.00347.2009. Learning is known to cause alterations in intrinsic cellular excitability but, to date, these changes have been seen only after multiple training trials. A powerful learning task that can be quickly acquired and extinguished with a single trial is fear conditioning. Rats were trained and extinguished on a hippocampus-dependent form of fear conditioning to determine whether learning-related changes in intrinsic excitability could be observed after a few training trials and a single extinction trial. Following fear training, hippocampal slices were made and intrinsic excitability was assayed via whole cell recordings from CA1 neurons. Alterations in intrinsic excitability, assayed by the postburst afterhyperpolarization and firing frequency accommodation, were observed after only three trials of contextual or trace-cued fear conditioning. Animals that had been trained in contextual and tracecued fear were then extinguished. Context fear-conditioned animals extinguished in a single trial and the changes in intrinsic excitability were reversed. Trace-cue conditioned animals only partially extinguished in a single trial and reductions in excitability remained. Thus a single learning experience is sufficient to alter intrinsic excitability. This dramatically extends observations of learning-specific changes in intrinsic neuronal excitability previously observed in paradigms requiring many training trials, suggesting the excitability changes have a basic role in acquiring new information.

Learning-related reductions of the postburst afterhyperpolarization (AHP) in hippocampal pyramidal neurons have been shown ex vivo, after trace eyeblink conditioning. The AHP is also reduced by many neuromodulators, such as norepinephrine, via activation of protein kinases. Trace eyeblink conditioning, like other hippocampus-dependent tasks, relies on protein synthesis for consolidating the learned memory. Protein kinase A (PKA) has been shown to be a key contributor for protein synthesis via the cAMP-response element-binding pathway. Here, we have explored a potential involvement of PKA and protein kinase C (PKC) in maintaining the learning-related postburst AHP reduction observed in CA1 pyramidal neurons. Bath application of isoproterenol (1 M), a ␤-adrenergic agonist that activates PKA, significantly reduced the AHP in CA1 neurons from control animals, but not from rats that learned. This occlusion suggests that PKA activity is involved in maintaining the AHP reduction measured ex vivo after successful learning. In contrast, bath application of the PKC activator, (-) indolactam V (0.2 M), significantly reduced the AHP in CA1 neurons from both control and trained rats, indicating that PKC activity is not involved in maintaining the AHP reduction at this point after learning.hippocampus ͉ protein kinase C ͉ trace eyeblink T he postburst afterhyperpolarization (AHP) has been repeatedly demonstrated ex vivo to be reduced in hippocampal pyramidal neurons after hippocampus-dependent learning, such as the trace eyeblink conditioning (EBC) task (1). Trace EBC is a hippocampus-dependent task (2-4) that, like others (5, 6), requires protein synthesis for learning and consolidation of the memory (7), yet the molecular cascade that underlies this learning-related AHP alteration after trace EBC has not been studied or identified.The postburst AHP is predominantly a Ca 2ϩ -dependent K ϩ current with 2 distinct components (8-10). The SK2 channels underlie the apamin-sensitive medium AHP (11-13) and have been shown to be intimately involved in regulating synaptic plasticity in dendritic spines along with NMDA receptors (14). The channel underlying the later, slow AHP has yet to be discovered; however, it is thought to be localized to the apical and basal dendrites in close proximity to the soma (15, 16). Because of its somatic localization, the slow AHP may play a significant role in the final somatic integration of synaptic inputs. Unless specified, we will be referring to both the medium and slow components of the AHP throughout the text. Activation of protein kinases via various neuromodulators reduces the AHP (10, 17). Specifically, activation of cholinergic and metabotropic glutamate receptors have been shown to reduce the AHP via protein kinase C (PKC) and Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) (18)(19)(20)(21)(22). Activation of monoamine receptors reduces the AHP via protein kinase A (PKA) (21, 23). In addition to reducing the AHP, all 3 kinases have been implicated in long-term potentiation (LTP), wi...

McKay BM, Oh MM, Galvez R, Burgdorf J, Kroes RA, Weiss C, Adelman JP, Moskal JR, Disterhoft JF. Increasing SK2 channel activity impairs associative learning.

The FVB/N (FVB) mouse has been a popular background strain for constructing transgenic mice. However, behavioral phenotyping of the resultant mice is complicated due to severe visual impairment in the FVB background strain. Previous studies reported cognitive impairments with the FVB strain, suggesting the background as unsuitable for behavioral analysis. In this study, we compared FVB mice to the well characterized C57BL/6 (B6) strain in a battery of hippocampus dependent tasks that had several non-visual cues. The tasks included: trace eyeblink conditioning, spontaneous alternation in the Y-maze, social recognition, trace and contextual fear conditioning, and odor habituation-dishabituation. FVB mice were able to learn all the tasks, often to similar levels as B6 mice. In contrast to previous reports, our data suggest FVB mice are not cognitively deficient with temporal memory tasks when the tasks do not rely heavily upon vision. Thus, the FVB strain may be used as the genetic background for behavioral phenotyping when non-visual hippocampal dependent tasks are utilized.