Abstract
Left-right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3-CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left-right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left-right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory.
Highlights
Left–right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere
A seminal discovery in the mouse brain suggests that left–right asymmetry may be a fundamental property of the mammalian hippocampus: it was found that the postsynaptic spine morphology and receptor distribution in CA1 pyramidal neurons is determined by whether the presynaptic input originates in the left or right CA3 [9, 10]
Apical CA1 postsynaptic spines receiving input from the left CA3 are primarily thin and rich in GluN2B subunit-containing NMDA receptors (NMDARs); in contrast, there is a higher proportion of mushroom-shaped spines receiving right CA3 projection, and these larger spines have a lower density of GluN2B subunit-containing NMDARs [9, 10]
Summary
Halorhodopsin Permits Effective and Reversible Acute Silencing of Dorsal CA3 Neurons in Vivo. We used optrode recordings in anesthetized mice to confirm that CA3 neurons in the dorsal hippocampus of eNpHR3.0-eYFP–expressing mice could be silenced by green light delivery for a duration equivalent to that of trials in the behavioral tasks; illumination was delivered via an optical fiber placed above the CA3 and in between the two injection sites. To ensure that unilateral optogenetic silencing does not cause a generalized sensorimotor or motivational behavioral impairment that could account for the deficit in the left-NpHR group on the spatial long-term memory task, a subset of the same mice, as well as a group of experimentally naïve mice, were trained on an associative, nonspatial visual discrimination T-maze task [16, 19] with trial-limited light delivery, as before (10–40 s). The expression of HFS-LTP depends on whether the input originates in the left or right CA3; this suggests that these two inputs may perform different functions in vivo and provides one possible mechanistic explanation for the observed functional lateralization in long-term memory
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