Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior

Abstract

The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the ''chandelier'' or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their in vivo activity patterns and influence over pyramidal cell dynamics are not well understood. We achieved cell-type-specific genetic access to AACs in mice and show that AACs in the hippocampal area CA1 are synchronously activated by episodes of locomotion or whisking during rest. Bidirectional intervention experiments in head-restrained mice performing a random foraging task revealed that AACs inhibit CA1 pyramidal cells, indicating that the effect of GABA on the initial segments in the hippocampus is inhibitory in vivo. Finally, optogenetic inhibition of AACs at specific track locations induced remapping of pyramidal cell place fields. These results demonstrate brain-state-specific dynamics of a critical inhibitory controller of cortical circuits.

Toward Understanding the Diverse Roles of Perisomatic Interneurons in Epilepsy

“…33,39,40 Similar trends were found on the time scale of seconds, during smaller activity fluctuations within behavioral states: while PVBC activity is strongly positively correlated to pyramidal cell activity, AAC activity is only weakly correlated and CCKBC activity is clearly negatively correlated (Figure 1c). 32,33 This latter observation is especially surprising because previous reports (lacking specific CCKBC labeling) suggested that interneuron activity typically scales positively with network activity, both in control and epileptic brains. Positively scaled, also known as balanced inhibition, contributes to stabilizing network dynamics across a wide range of activity levels.…”

“… 32 AACs are recruited during theta-, but not during ripple oscillations. 33 , 39 , 40 Similar trends were found on the time scale of seconds, during smaller activity fluctuations within behavioral states: while PVBC activity is strongly positively correlated to pyramidal cell activity, AAC activity is only weakly correlated and CCKBC activity is clearly negatively correlated ( Figure 1c ). 32 , 33 …”

“…As a result, interneuron type-specific transgenic mouse lines or synthetic viral enhancers are rapidly becoming available, 27 - 31 including transgenic lines for selectively labeling CCKBCs (Sncg-Flp) 32 or AACs (Nkx2.1-CreER, Unc5b-CreER, or Vipr2-Cre). 27 , 33 , 34 …”

“… 64 For example, extreme chloride accumulation inside glutamatergic neurons may produce excitatory GABAergic responses and contribute to epileptic seizures. 65 - 68 While AAC activation suppresses CA1 pyramidal cell spiking in non-epileptic mice in vivo , 33 whether AACs have excitatory or inhibitory effects in epilepsy remains to be determined.…”

Cholecystokinin-expressing (CCK+) basket cells are key controllers of theta-gamma coupled rhythms in the hippocampus

“…On the one hand, we very much need cellular-based network models to help us untangle the various facets of the interacting dynamics of the network system that produces theta and gamma rhythms and their coupling as this cannot come from experiments alone. Simply identifying and targeting the many different inhibitory cell types during ongoing behaviours and rhythmic activities is an immense, ongoing experimental challenge that is extremely laborious [36][37][38] . On the other hand, the presence of nonlinearity, high-dimensionality and degeneracy in detailed models makes it difficult to extract explicit mechanisms.…”