Hippocampal CA1 Circuitry Dynamically Gates Direct Cortical Inputs Preferentially at Theta Frequencies

Abstract

Hippocampal CA1 pyramidal neurons receive intrahippocampal and extrahipppocampal inputs during theta cycle, whose relative timing and magnitude regulate the probability of CA1 pyramidal cell spiking. Extrahippocampal inputs, giving rise to the primary theta dipole in CA1 stratum lacunosum moleculare, are conveyed by the temporoammonic pathway. The temporoammonic pathway impinging onto the CA1 distal apical dendritic tuft is the most electrotonically distant from the perisomatic region yet is critical in regulating CA1 place cell activity during theta cycles. How does local hippocampal circuitry regulate the integration of this essential, but electrotonically distant, input within the theta period? Using whole-cell somatic recording and voltage-sensitive dye imaging with simultaneous dendritic recording of CA1 pyramidal cell responses, we demonstrate that temporoammonic EPSPs are normally compartmentalized to the apical dendritic tuft by feedforward inhibition. However, when this input is preceded at a one-half theta cycle interval by proximally targeted Schaffer collateral activity, temporoammonic EPSPs propagate to the soma through a joint, codependent mechanism involving activation of Schaffer-specific NMDA receptors and presynaptic inhibition of GABAergic terminals. These afferent interactions, tuned for synaptic inputs arriving one-half theta interval apart, are in turn modulated by feedback inhibition initiated via axon collaterals of pyramidal cells. Therefore, CA1 circuit integration of excitatory inputs endows the CA1 principal cell with a novel property: the ability to function as a temporally specific "AND" gate that provides for sequence-dependent readout of distal inputs.

Massive and Specific Dysregulation of Direct Cortical Input to the Hippocampus in Temporal Lobe Epilepsy

“…3A). Consistent with our previous studies (Ang et al, 2005), these results demonstrate that feedforward inhibition spatially compartmentalizes temporoammonic pathway activity to the distal dendrites of CA1 neurons.…”

“…A 4ϫ objective lens (0.28 numerical aperture; Olympus, Tokyo, Japan) imaged a 2.5 ϫ 2.5 mm region in hippocampal area CA1 (32 ϫ 32 m region imaged per pixel). Similar to previous studies (Ang et al, 2005), we demonstrate a close correlation of the voltage-sensitive dye response with the simultaneous recordings from the apical dendrite in stratum radiatum, in response to Schaffer collateral stimulation (supplemental Fig. 1 B, available at www.jneurosci.org as supplemental material).…”

“…This inhibition, evoked synaptically by temporoammonic afferent stimulation, plays an important role in limiting cell firing. Blockade of inhibition unmasks a strong excitation in CA1 pyramidal cells after activation of the temporoammonic pathway (Ang et al, 2005). In animals with chronic epilepsy, a partial loss of feedforward inhibition could produce a loss of spatial segregation of temporoammonic inputs, resulting in strong depolarization of the CA1 dendrites and soma.…”

“…In addition to being regulated by powerful feedforward inhibition, this pathway is also extensively and selectively gated by specific sets of feedback interneurons, the oriens/alveus interneurons, which are activated by CA1 pyramidal neurons, and project powerfully to the afferent innervation zone of the temporoammonic input, stratum lacunosum/moleculare (termed OA-SLM interneurons). Once CA1 neurons activate, these OA-SLM interneurons will normally shut off the temporoammonic input in a feedback manner, preventing reentrant activation and further regulating this pathway (Lacaille et al, 1987;Yanovsky et al, 1997;Ang et al, 2005). However, in epileptic animals, these interneurons are selectively lost (Houser and Esclapez, 1996;Morin et al, 1998;Dinocourt et al, 2005), which would remove a further check on this pathway, allowing reentrant activity to proceed unchecked.…”

“…This animal model shares a natural history of develop-ment with human TLE in that it is characterized by a latent or silent period between the pilocarpine-induced initial injury and the onset of recurrent seizures, as well as shared neuropathology (French et al, 1993;Spencer and Spencer, 1994). High-speed voltage-sensitive dye imaging offers sufficient spatial and temporal resolution to record simultaneously membrane potential changes in 6400 voltage sensors at high sampling frequency (1-2 kHz) Salzberg et al, 1973;Contreras and Llinás, 2001;Ang et al, 2005), which enables coincident recording of afferent, intrinsic and efferent responses after synaptic activation in multiple hippocampal circuits.…”