Differential maintenance and frequency-dependent tuning of LTP at hippocampal synapses of specific strains of inbred mice

Transgenic and knockout mice are used extensively to elucidate the molecula r mechanisms of hippocampal synaptic plasticity. However, genetic and pheno typic variations between inbred mouse strains that are used to construct ge netic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recor ding methods, we compared the membrane biophysical, cellular electrophysiol ogical, and synaptoplastic properties of hippocampal CA1 neurons in four sp ecific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hi ppocampal long-term potentiation (LTP) induced by theta-pattern stimulation , and by repeated multi-burst 100-Hz stimulation at various interburst inte rvals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenanc e of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was sign ificantly enhanced in129/ SvEms slices, but not in DBA and CBA slices. Long -term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons sh owed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synap tically-evoked glutamatergic postsynaptic currents did not significantly di ffer among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduce d hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitat ion induced by forskolin (an activator of adenylate cyclase) and IBMX (a ph osphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic f acilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not i n BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic faci litation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some in bred mouse strains may be "tuned" to particular temporal patterns of synapt ic activity. From a broader perspective, our data support the notion that s train-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use g enetically modified mice to explore the molecular bases of synaptic plastic ity.