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We combined electrical perforant pathway stimulation with electrophysiological and fMRI recordings in the hippocampus to investigate the effects of neuronal afterdischarges (nAD) on subsequent fMRI BOLD signals in the presence of isoflurane and medetomidine. These two drugs already alter basal hemodynamics in the hippocampus, with isoflurane being mildly vasodilatory and medetomidine being mildly vasoconstrictive. The perforant pathway was stimulated once for 8 seconds with either continuous 20 Hz pulses (continuous stimulation) or 8 bursts of 20 high-frequency pulses (burst stimulation). Burst stimulation in the presence of medetomidine elicited long-lasting nAD that coincided with a brief positive BOLD response and a subsequent long-lasting decrease in BOLD signals. Under isoflurane, this stimulation elicited only short-lasting nAD and only a short-lasting decline in BOLD signals. In contrast, continuous stimulation under isoflurane and medetomidine caused a similar duration of nAD. Under isoflurane, this caused only a sharp and prolonged decline in BOLD signals, whereas under medetomidine, again, only a brief positive BOLD response was elicited, followed by a shorter and moderate decline in BOLD signals. Our results suggest that nAD simultaneously activate different neurovascular coupling mechanisms that then independently alter local hemodynamics in the hippocampus, resulting in an even more complex neurovascular coupling mechanism.

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Repeated high-frequency pulse-burst stimulations of the rat perforant pathway elicited positive BOLD responses in the right hippocampus, septum and prefrontal cortex. However, when the first stimulation period also triggered neuronal afterdischarges in the hippocampus, then a delayed negative BOLD response in the prefrontal cortex was generated. While neuronal activity and cerebral blood volume (CBV) increased in the hippocampus during the period of hippocampal neuronal afterdischarges (h-nAD), CBV decreased in the prefrontal cortex, although neuronal activity did not decrease. Only after termination of h-nAD did CBV in the prefrontal cortex increase again. Thus, h-nAD triggered neuronal activity in the prefrontal cortex that counteracted the usual neuronal activity-related functional hyperemia. This process was significantly enhanced by pilocarpine, a mACh receptor agonist, and completely blocked when pilocarpine was co-administered with scopolamine, a mACh receptor antagonist. Scopolamine did not prevent the formation of the negative BOLD response, thus mACh receptors modulate the strength of the negative BOLD response.

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The effects of hippocampal neuronal afterdischarges (nAD) on hemodynamic parameters, such as blood-oxygen-level-dependent (BOLD) signals) and local cerebral blood volume (CBV) changes, as well as neuronal activity and metabolic parameters in the dentate gyrus, was investigated in rats by combining in vivo electrophysiology with functional magnetic resonance imaging (fMRI) or 1H-nuclear magnetic resonance spectroscopy (1H-NMRS). Brief electrical high-frequency pulse-burst stimulation of the right perforant pathway triggered nAD, a seizure-like activity, in the right dentate gyrus with a high incidence, a phenomenon that in turn caused a sustained decrease in BOLD signals for more than 30 min. The decrease was associated with a reduction in CBV but not with signs of hypoxic metabolism. nAD also triggered transient changes mainly in the low gamma frequency band that recovered within 20 min, so that the longer-lasting altered hemodynamics reflected a switch in blood supply rather than transient changes in ongoing neuronal activity. Even in the presence of reduced baseline BOLD signals, neurovascular coupling mechanisms remained intact, making long-lasting vasospasm unlikely. Subsequently generated nAD did not further alter the baseline BOLD signals. Similarly, nAD did not alter baseline BOLD signals when acetaminophen was previously administered, because acetaminophen alone had already caused a similar decrease in baseline BOLD signals as observed after the first nAD. Thus, at least two different blood supply states exist for the hippocampus, one low and one high, with both states allowing similar neuronal activity. Both acetaminophen and nAD switch from the high to the low blood supply state. As a result, the hemodynamic response function to an identical stimulus differed after nAD or acetaminophen, although the triggered neuronal activity was similar.

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Persistent firing is believed to be a cellular correlate of working memory. While the effects of noradrenaline (NA) on working memory have widely been described, its effect on the cellular mechanisms of persistent firing remains largely unknown. Using in vitro intracellular recordings, we demonstrate that persistent firing is supported by individual neurons in hippocampal CA1 pyramidal cells through cholinergic receptor activation, but is dramatically attenuated by NA. In contrast to the classical theory that recurrent synaptic excitation supports persistent firing, suppression of persistent firing by NA was independent of synaptic transmission, indicating that the mechanism is intrinsic to individual cells. In agreement with detrimental effects of cAMP on working memory, we demonstrate that the suppressive effect of NA was through cAMP-PKA pathway. In addition, activation of ß1 and/or ß3 adrenergic receptors, which increases cAMP levels, suppressed persistent firing. These results are in line with working memory decline observed during high levels of NA and cAMP, which are implicated in high stress, aging, and schizophrenia.

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Persistent neural activity has been observed in vivo during working memory tasks, and supports short-term (up to tens of seconds) retention of information. While synaptic and intrinsic cellular mechanisms of persistent firing have been proposed, underlying cellular mechanisms are not yet fully understood. In vitro experiments have shown that individual neurons in the hippocampus and other working memory related areas support persistent firing through intrinsic cellular mechanisms that involve the transient receptor potential canonical (TRPC) channels. Recent behavioral studies demonstrating the involvement of TRPC channels on working memory make the hypothesis that TRPC driven persistent firing supports working memory a very attractive one. However, this view has been challenged by recent findings that persistent firing in vitro is unchanged in TRPC knock out (KO) mice. To assess the involvement of TRPC channels further, we tested novel and highly specific TRPC channel blockers in cholinergically induced persistent firing in mice CA1 pyramidal cells for the first time. The application of the TRPC4 blocker ML204, TRPC5 blocker clemizole hydrochloride, and TRPC4 and 5 blocker Pico145, all significantly inhibited persistent firing. In addition, intracellular application of TRPC4 and TRPC5 antibodies significantly reduced persistent firing. Taken together these results indicate that TRPC4 and 5 channels support persistent firing in CA1 pyramidal neurons. Finally, we discuss possible scenarios causing these controversial observations on the role of TRPC channels in persistent firing.

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Working memory is a crucial ability we use in daily life. However, the cellular mechanisms supporting working memory still remain largely unclear. A key component of working memory is persistent neural firing which is believed to serve short-term (hundreds of milliseconds up to tens of seconds) maintenance of necessary information. In this review, we will focus on the role of transient receptor potential canonical (TRPC) channels as a mechanism underlying persistent firing. Many years of in vitro work have been suggesting a crucial role of TRPC channels in working memory and temporal association tasks. If TRPC channels are indeed a central mechanism for working memory, manipulations which impair or facilitate working memory should have a similar effect on TRPC channel modulation. However, modulations of working memory and TRPC channels were never systematically compared, and it remains unanswered whether TRPC channels indeed contribute to working memory in vivo or not. In this article, we review the effects of G-protein coupled receptors (GPCR) and neuromodulators, including acetylcholine, noradrenalin, serotonin and dopamine, on working memory and TRPC channels. Based on comparisons, we argue that GPCR and downstream signaling pathways that activate TRPC, generally support working memory, while those that suppress TRPC channels impair it. However, depending on the channel types, areas, and systems tested, this is not the case in all studies. Further work to clarify involvement of specific TRPC channels in working memory tasks and how they are affected by neuromodulators is still necessary in the future.

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