Hippocampal Lateralization and Synaptic Plasticity in the Intact Rat: No Left-Right Asymmetry in Electrically Induced CA3-CA1 Long-Term Potentiation

Abstract

The hippocampus is not a unitary, homogeneous brain area. Anatomical and functional specialization is evident along the septotemporal axis of the structure, and between the left and right hemispheres. In the mouse brain, a left-right asymmetry has been discovered in the plasticity of CA3-CA1 projections originating in the left versus right hippocampus. Presynaptic afferents originating in the left hemisphere-including both uncrossed Schaffer collaterals, and crossed commissural projections to the contralateral CA1-form small, plastic synapses, whereas afferents originating in right CA3 contact larger, less plastic, synapses. Studies using optogenetic techniques to selectively activate fibers originating from one hemisphere in ex vivo slices have revealed that projections originating from left CA3 exhibit a far greater capacity for long-term potentiation (LTP) of synaptic strength than those originating on the right. However, corresponding data from rats are currently unavailable, leaving open the question of species differences in hippocampal symmetry. In the current study, we reanalyzed data from our previous in vivo LTP work to address this issue. We analyzed plasticity in independent Schaffer collateral and commissural projections to CA1 originating from left and right CA3 in male Lister-hooded rats. However, we found no differences in the magnitude and duration of LTP induced in either crossed or uncrossed pathways following high-frequency tetanization of left versus right CA3. This contrast with previous findings may stem from methodological differences between in vivo electrical and ex vivo optogenetic approaches, but may reflect a genuine species difference in the organization and laterality of the rodent CA3-CA1 system.

Keywords: LTP; Schaffer collateral; commissural; hippocampus; in vivo; synaptic plasticity.

Fig. 1

(A) Photomicrograph at the approximate AP location of the stimulation (S) and recording (R) electrodes. (B) Schematic illustration of the hippocampus, showing recording electrode locations (R), stimulating electrode locations (S), and pathways stimulated. In reality, CA3 stimulating electrodes were placed 0.3 mm anterior to CA1 recording electrodes, as well as 0.5 mm laterally. The path of the crossed commissural projections is not intended to be anatomically faithful; these projections travel via the ventral hippocampal commissure, and cannot be represented in a coronal section. Examples of fEPSPs recorded in the left hippocampus in response to ipsilateral left CA3-CA1 Schaffer collateral stimulation (LHS S) and contralateral right CA3-CA1 commissural stimulation (RHS S) are shown. (C) Cartoon of the four pathways analyzed in this study: left (blue) and right (green) uncrossed CA3-CA1 Schaffer collateral projections, left-to-right CA3-CA1 commissural projections (blue), and right-to-left CA3-CA1 commissural projections (green). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

LTP induced by a strong tetanus. (A) Time course of LTP (relative to a tetanus at time ‘zero’) induced by a strong tetanus to left CA3 (left-hand panels) versus right CA3 (right-hand panels). Uncrossed Schaffer collateral pathways [top panels; n = 10 (left) and n = 16 (right)] and crossed commissural projections [bottom panels; n = 12 (left) and n = 17 (right)] are plotted separately. The illustration accompanying each graph shows the relevant pathway in red. The shaded areas indicate PTP (0-5 min post-tetanus); early LTP (E-LTP; 30-60 min post-tetanus) and late LTP (L-LTP; 4-5 h post-tetanus). (B) Percentage PTP, early LTP and late LTP in all 4 pathways. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

LTP induced by a weak tetanus. (A) Time course of LTP (relative to a tetanus at time ‘zero’) induced by a weak tetanus to left CA3 (left-hand panels) versus right CA3 (right-hand panels). Uncrossed Schaffer collateral pathways [top panels; n = 5 (left); n = 6 (right)] and crossed commissural projections [bottom panels; n = 4 (left); n = 8 (right)] are plotted separately. The illustration accompanying each graph shows the relevant pathway in red. The shaded areas indicate PTP (0-5 min post-tetanus); early LTP (E-LTP; 30-60 min post-tetanus) and late LTP (L-LTP; 4-5 h post-tetanus).(B) Percentage PTP, early LTP and late LTP (4–5 h post tetanus) in all 4 pathways. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

(A) Crossed-pathway stimulation of contralateral CA3 followed by ipsilateral CA3 at an interval of 50 ms did not result in PPF of fEPSPs recorded in ipsilateral CA1. An example of an ipsilateral CA3-CA1 fEPSP is shown without prior stimulation of the contralateral pathway (upper trace) and with prior contralateral stimulation (lower trace). The pulse-width was 0.2 ms in these examples, and the black arrow indicates the relevant comparison for the calculation of PPF. The schematic figures below the traces indicate that, in this example, the crossed pathway originated in right CA3, whereas the ipsilateral pathway originated in left CA3. The graph below shows percentage PPF as a function of pulse-width (B) Paired pulses delivered to the ipsilateral Schaffer collateral pathway at an interval of 50 ms caused robust PPF. An example is shown at a pulse-width of 0.2 ms; the black arrow highlights the key comparison between the slope of the first and second fEPSPs. The schematic figures below the trace indicates that, in this example, paired stimulation was delivered to the left CA3-CA1 projection. The graph below shows percentage PPF as a function of pulse-width. PPF declined with increasing pulse-width, but robust PPF was observed in all rats at pulse-widths of 0.1 and 0.2 ms.

Fig. 5

LFP activity in the left and right hippocampus of the same animals. (A) Samples of raw LFP trace illustrating corresponding episodes of LIA and theta activity in the left and right hippocampus of the same rat. (B) Mean time–frequency spectrum over the 60-min baseline period before the first tetanus in the left and right hippocampus (left and right panels respectively; n = 20). Each plot comprises 30 2-s samples of LFP recorded at 2-min intervals, and averaged across all 20 animals. (C) Mean power spectral density in log units [log₁₀(µV²/Hz)] averaged over the full 1-h baseline period, and plotted as a function of frequency (log scale) for both left and right hippocampus (left and right panels respectively; n = 20). The shaded area represents ± 1 SEM.