Proximodistal Organization of the CA2 Hippocampal Area

Fernández-Lamo, Iván; Gómez-Domínguez, Daniel; Sánchez-Aguilera, Alberto; Cid, Elena; Valero, Manuel; Prida, Liset Menéndez de la

doi:10.2139/ssrn.3192037

Cited by 7 publications

(11 citation statements)

References 53 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this idea, DGC recruitment of FFI in CA3/CA2 is randomly wired so as to provide blanket inhibition and govern network excitability in CA3 and CA2, rather than couple individual DGC-dependent excitation with inhibition onto distinct populations of pyramidal neurons (Neubrandt et al, 2017). Loss of PV IN mediated inhibition may disrupt neuronal ensembles and network oscillations by impairing neuronal spiking, recurrent excitation in CA3 networks (Sadeh and Clopath, 2021), reciprocal inhibition between CA3 and CA2 (Boehringer et al, 2017;Fernandez-Lamo et al, 2019;Lehr et al, 2021;Middleton and McHugh, 2020;Nasrallah et al, 2019;Stober et al, 2020) and/or the balance between subcortical and entorhinal inputs to CA3/CA2 during encoding of social stimuli (Chen et al, 2020;Lopez-Rojas et al, 2022;Robert et al, 2021;Wu et al, 2021). Future studies will edify how PV inhibition of CA3/CA2 facilitates encoding of social stimuli in CA3 and CA2 neuronal ensembles and network oscillations.…”

Section: Discussionmentioning

confidence: 97%

An inhibitory circuit-based enhancer of Dyrk1a function reversesDyrk1a-associated impairment in social recognition

Sahay

Shi

Alipio

2023

Preprint

View full text Add to dashboard Cite

Heterozygous mutations in the Dual specificity tyrosine-phosphorylation-regulated kinase 1a Dyrk1a gene define a syndromic form of Autism Spectrum Disorder. The synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition are unclear. Here, we identify a social experience-sensitive mechanism in hippocampal mossy fiber-parvalbumin interneuron (PV IN) synapses by which Dyrk1a recruits feed-forward inhibition of CA3 and CA2 to promote social recognition. We employ genetic epistasis logic to identify a cytoskeletal protein, Ablim3, as a synaptic substrate of Dyrk1a. We demonstrate that Ablim3 downregulation in dentate granule cells of adult hemizygous Dyrk1a mice is sufficient to restore PV IN mediated inhibition of CA3 and CA2 and social recognition. Acute chemogenetic activation of PV INs in CA3/CA2 of adult hemizygous Dyrk1a mice also rescued social recognition. Together, these findings illustrate how targeting Dyrk1a synaptic and circuit substrates as enhancers of Dyrk1a function harbors potential to reverse Dyrk1a haploinsufficiency-associated circuit and cognition impairments.

show abstract

Section: Discussionmentioning

confidence: 97%

An inhibitory circuit-based enhancer of Dyrk1a function reversesDyrk1a-associated impairment in social recognition

Sahay

Shi

Alipio

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Therefore, the CA2b/CA3a border was drawn at the approximate halfway point of the intermingled region, so as to balance the exclusion of CA2b neurons against the inclusion of CA3a neurons. Considering recent evidence for proximodistal heterogeneity within the CA2 region (Fernandez-lamo et al, 2019; Okamoto & Ikegaya, 2018), and our own observations of greater resilience to neurodegeneration in distal CA2, the CA2 subfield was divided into two equal halves designated as CA2a (distal, near CA1) and CA2b (proximal, near CA3). Such a subdivision of the CA2 subfield has been proposed as a means to take into account the anatomical distinctions between the proximal and distal ends of CA2, considering that neurons in the latter region do not colocalize with the DG mossy fibers (Dudek, Alexander, & Farris, 2016; Fernandez-lamo et al, 2019; Okamoto & Ikegaya, 2018).…”

Section: Methodsmentioning

confidence: 99%

Reduced cholecystokinin-expressing interneuron input contributes to disinhibition of the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

Whitebirch

Barnett

Santoro

et al. 2022

Preprint

View full text Add to dashboard Cite

A significant proportion of temporal lobe epilepsy (TLE) patients experience drug-resistant seizures associated with mesial temporal sclerosis, in which there is extensive cell loss in the hippocampal CA1 and CA3 subfields, with a relative sparing of dentate gyrus granule cells and the CA2 pyramidal neurons. A role for CA2 in seizure generation was suggested based on findings of a reduction in synaptic inhibition (Williamson & Spencer, 1994) and the presence of interictal-like spike activity in resected hippocampal tissue from TLE patients (Wittner et al., 2009). We recently found that in the pilocarpine-induced status epilepticus mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al., 2022). In the present study we explored the basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches. We report a widespread decrease in the density of pro-cholecystokinin-immunopositive interneurons and a functional impairment of cholecystokinin-expressing interneuron-mediated inhibition of CA2 pyramidal neurons. We also found a decrease in the density of CA2 parvalbumin-immunopositive interneurons and disruption to the pyramidal neuron-associated perisomatic perineuronal net in the CA2 subfield. These data reveal a set of pathological alterations that may disrupt inhibition of CA2 pyramidal neurons and their downstream targets in epileptic mice.

show abstract

“…While such a detailed characterization is still missing for CA2, several studies have analyzed the broad gamma modulation of CA2 firing. CA2 pyramidal cells display phase locking to a wide range of frequencies in the gamma band (Alexander et al, 2018; Fernandez‐Lamo et al, 2019), and CA2 silencing for long periods of time preferentially affects the low gamma band component in CA1 (Alexander et al, 2018). Interestingly, theta modulation strength increases across CA1 towards the border with CA2, while gamma modulation displays an opposite trend (Fernandez‐Lamo et al, 2019).…”

Section: Theta Gamma and Neuromodulatory Control Of Ca2 Network Dynamicsmentioning

confidence: 99%

CA2 orchestrates hippocampal network dynamics

2022

View full text Add to dashboard Cite

The hippocampus is composed of various subregions: CA1, CA2, CA3, and the dentate gyrus (DG). Despite the abundant hippocampal research literature, until recently, CA2 received little attention. The development of new genetic and physiological tools allowed recent studies characterizing the unique properties and functional roles of this hippocampal subregion. Despite its small size, the cellular content of CA2 is heterogeneous at the molecular and physiological levels. CA2 has been heavily implicated in social behaviors, including social memory. More generally, the mechanisms by which the hippocampus is involved in memory include the reactivation of neuronal ensembles following experience. This process is coordinated by synchronous network events known as sharp‐wave ripples (SWRs). Recent evidence suggests that CA2 plays an important role in the generation of SWRs. The unique connectivity and physiological properties of CA2 pyramidal cells make this region a computational hub at the core of hippocampal information processing. Here, we review recent findings that support the role of CA2 in coordinating hippocampal network dynamics from a systems neuroscience perspective.

show abstract

Proximodistal Organization of the CA2 Hippocampal Area

Cited by 7 publications

References 53 publications

An inhibitory circuit-based enhancer of Dyrk1a function reversesDyrk1a-associated impairment in social recognition

An inhibitory circuit-based enhancer of Dyrk1a function reversesDyrk1a-associated impairment in social recognition

Reduced cholecystokinin-expressing interneuron input contributes to disinhibition of the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

CA2 orchestrates hippocampal network dynamics

Contact Info

Product

Resources

About