Abstract
Reduced inhibitory GABA function, so-called neural disinhibition, has been implicated in cognitive disorders, including schizophrenia and age-related cognitive decline. We previously showed in rats that hippocampal disinhibition by local microinfusion of the GABA-A receptor antagonist picrotoxin disrupted memory and attention and enhanced hippocampal multi-unit burst firing recorded around the infusion site under isoflurane anesthesia. Here, we analyzed the hippocampal local field potential (LFP) recorded alongside the multi-unit data. We predicted frequency-specific LFP changes, based on previous studies implicating GABA in hippocampal oscillations, with the weight of evidence suggesting that disinhibition would facilitate theta and disrupt gamma oscillations. Using a new semi-automated method based on the kurtosis of the LFP peak-amplitude distribution as well as on amplitude envelope thresholding, we separated three distinct hippocampal LFP states under isoflurane anesthesia: "burst" and "suppression" states-high-amplitude LFP spike bursts and the interspersed low-amplitudeperiods-and a medium-amplitude "continuous" state. The burst state showed greater overall power than suppression and continuous states and higher relative delta/theta power, but lower relative beta/gamma power. The burst state also showed reduced functional connectivity across the hippocampal recording area, especially around theta and beta frequencies. Overall neuronal firing was higher in the burst than the other two states, whereas the proportion of burst firing was higher in burst and continuous states than the suppression state. Disinhibition caused state- and frequency-dependent LFP changes, tending to increase power at lower frequencies (<20 Hz), but to decrease power and connectivity at higher frequencies (>20 Hz) in burst and suppression states. The disinhibition-induced enhancement of multi-unit bursting was also state-dependent, tending to be more pronounced in burst and suppression states than the continuous state. Overall, we characterized three distinct hippocampal LFP states in isoflurane-anesthetized rats. Disinhibition changed hippocampal LFP oscillations in a state- and frequency-dependent way. Moreover, the disinhibition-induced enhancement of multi-unit bursting was also LFP state-dependent.
Highlights
These states are characterized by different local field potential (LFP) properties and associated multi-unit activity (MUA), which are consistent with the properties of burst-suppression and “activated” or “light-anesthesia” hippocampal LFP states that have previously been identified based on visual inspection and other methods (Table 2)
Our finding that the enhanced hippocampal multi-unit burst firing induced by hippocampal picrotoxin infusion is more pronounced in the burst and suppression state, compared to the continuous state, is consistent with previous studies suggesting that the burst and suppression states are characterized by neuronal hyperexcitability (Ferron et al, 2009; Kroeger & Amzica, 2007; Land et al, 2012)
Cortical, including hippocampal, LFP oscillations have been suggested to be important for memory and other cognitive functions, and alterations of such oscillations have been linked to memory and other cognitive impairments (Buzsáki & Draguhn, 2004; Colgin, 2016; Uhlhaas & Singer, 2006, 2010)
Summary
Subconvulsive neural disinhibition, that is, reduced inhibitory GABA function, within the hippocampus has been implicated in important neuropsychiatric disorders, including schizophrenia and age-related cognitive decline, and in the cognitive impairments characterizing these disorders (Bast, Pezze, & McGarrity, 2017; Benes & Berretta, 2001; Heckers & Konradi, 2015; McGarrity, Mason, Fone, Pezze, & Bast, 2017; Nava-Mesa, Jiménez-Díaz, Yajeya, & NavarroLopez, 2014; Palop & Mucke, 2016; Stanley, Fadel, & Mott, 2012; Thomé, Gray, Erickson, Lipa, & Barnes, 2016). Substantial evidence suggests that theta and gamma LFP rhythms depend on hippocampal GABAergic inhibition; this evidence leads to the hypotheses underlying our study of the LFP changes caused by hippocampal disinhibition and will be considered in the following paragraphs. Another prominent hippocampal rhythm, sharp-wave ripples (110–250 Hz ripples superimposed on 0.01–3 Hz sharp waves; Colgin, 2016), will not be considered further in this article, because ripples are not expressed under volatile anesthetics (Ylinen et al, 1995), and the frequency range of our LFP recordings (0.7–170 Hz) did not encompass the full range of sharp waves and ripples. We examined if the disinhibition-induced enhancement of multi-unit burst firing reported previously (McGarrity et al, 2017) is dependent on the LFP state
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