Selective Modification of Short-Term Hippocampal Synaptic Plasticity and Impaired Memory Extinction in Mice with a Congenitally Reduced Hippocampal Commissure

Abstract

The hippocampus is critical for forming new long-term memories, but the contributions of the hippocampal commissure (HC) to memory function and hippocampal synaptic plasticity are unclear. To shed light on this issue, we characterized behavioral memory and hippocampal synaptic plasticity in two inbred mouse strains. BALB/cWah1 mice display a range of corpus callosal defects and an intact HC, whereas 9XCA/Wah mice exhibit a complete absence of corpus callosum and a greatly reduced HC. No differences between strains were found in long-term potentiation (LTP) within two synaptic pathways in hippocampal slices. However, paired-pulse facilitation was deficient in area CA1 of slices from 9XCA/Wah, and it was rescued by decreasing extracellular [Ca 2ϩ ], suggesting that presynaptic calcium dynamics may be altered in this strain. In addition, contextual fear extinction was impaired in 9XCA/Wah mice, but performance on cued fear extinction and on 24 hr memory tests for cued and contextual fear conditioning were not significantly different between strains. Thus, an intact HC is critical for normal extinction of contextual fear. Intact interhemispheric connectivity is not required for acquisition or expression of cued and contextual fear conditioning. LTP was normal in slices from mice that lacked an intact HC, and this was correlated with normal performance on fear conditioning tests. In contrast, impaired short-term synaptic plasticity was correlated with defective contextual memory extinction in mice lacking an intact HC. Thus, the HC in mice is vital for particular aspects of memory function and for short-term synaptic modification in specific hippocampal circuits. Key words: hippocampal commissure; memory; learning; LTP; fear conditioning; extinction; agenesis; mouse strains; synaptic plasticityThe classic case study of H.M., a patient with surgical transection of the medial temporal lobes, demonstrated that the hippocampus is critical for the formation of new declarative memories (Scoville and Milner, 1957). Studies of human commissurotomy patients indicate that the main interhemispheric communication pathway between hippocampi, the hippocampal commissure (HC), is important for normal memory function. Indeed, patients with a transected HC show greater recognition memory deficits than those with an intact HC (Phelps et al., 1991). Patients with transection of both the corpus callosum (CC) and the HC also showed poor memory performance (Zaidel and Sperry, 1974). These findings indicate that an intact CC and HC are required for normal memory function.In two common inbred mouse strains, BALB/c and 129, agenesis of the CC occurs in Ͻ50% of these mice, whereas the remainder appear to have normal forebrain commissures (see Fig.

Hippocampal Mek/Erk signaling mediates extinction of contextual freezing behavior

“…Notably, among multiple responses elicited by fear states, context-specific freezing has been proposed as one of the main risks factors for the development of anxiety disorders (Buss et al, 2004). Impaired extinction of freezing to contextual stimuli has been observed in mouse strains with reduced hippocampal commissure (Schimanski et al, 2002). Supporting this view, we have recently shown that hippocampal mechanisms encompassing actin rearrangement are required for contextual fear extinction (Fischer et al, 2004) in this paradigm.…”

Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+ tf/tf has severely reduced hippocampal commissure and absent corpus callosum

“…BTBR mice may prove especially valuable for investigating the role of the hippocampal commissure. The 9XCA/ Wah recombinant strain with severely reduced HC has an interesting deficit in paired-pulse facilitation of LTP in the hippocampal slice as well as slower extinction of con-textual conditioning [17]. If these deficits arise from the anatomical insufficiency of commissural inputs, then we would expect to observe similar deficits in BTBR.…”

β-Adrenergic Receptor Activation Facilitates Induction of a Protein Synthesis-Dependent Late Phase of Long-Term Potentiation

“…fEPSPs were obtained by stimulating the Schaeffer collateral-commissural fibers with a bipolar nickel-chromium electrode (130 m diameter). Stimulation intensity (0.08 ms pulse duration) was adjusted to evoke fEPSP amplitudes that were 40% of maximal size (Schimanski et al, 2002;Woo and Nguyen, 2003). Subsequent fEPSPs were elicited at the rate of once per minute at this "test" stimulation intensity.…”