Acute systemic MK‐801 induced functional uncoupling between hippocampal areas CA3 and CA1 with distant effect in the retrosplenial cortex

Abstract

The hippocampus and retrosplenial cortex are integrated within a higher-order cognitive circuit supporting relational (spatial, contextual, episodic) forms of learning and memory. Hippocampal place cells can coordinate multiple parallel representations in the same physical environment. Novel environment exploration triggers expression of immediate-early genes (IEGs) Arc and Homer1a in spatial context-specific ensembles of CA1 and CA3 neurons. Less is know about ensemble coding in the retrosplenial cortex (RSC), a region directly connected and functionally coupled to CA1. Hippocampal and retrosplenial damage is found in patients with schizophrenia alongside cognitive deficits affecting relational memory. Systemic administration of non-competitive NMDAR antagonists such as MK-801 is used to model psychosis in animals and humans. Acute systemic MK-801 (0.15 mg/kg) impaired cognitive control in rats and ensemble code for spatial context in CA1. Here, we use expression of immediate-early genes Arc and Homer 1a to examine ensemble coding in rat CA3 and RSC to test if the effect of MK-801 extends upstream and downstream of CA1, respectively. Different rats explored the same context twice (A/A), explored two distinct contexts (A/B) or remained in their home cage (CC). In contrast to CA1, MK-801 did not affect ensemble coding in CA3. Unlike CA3 and CA1, similarity of RSC ensembles active during exploration did not reflect change in spatial context, but MK-801 (0.15 mg/kg) increased similarity in RSC ensembles active during spontaneous behavior in the home cage. The data provide support for MK-801-induced functional uncoupling between CA3 and CA1 and suggest that ensemble coding deficit may extend downstream of CA1. This deficit may reflect hyperassociative state in the cognitive circuit underlying cognitive disorganization in psychosis. © 2016 Wiley Periodicals, Inc.

Neural and neuronal discoordination in schizophrenia: From ensembles through networks to symptoms

“…Since fast frequency gamma coordinates CA1 activity with its major afferent input from the medial EC, this indicates a predominance of input from the EC at the expense of input from CA3 . As already mentioned, decreased communication (ie, uncoupling) between CA1 and CA3 subregions after MK‐801 was also observed using immediate early gene expression . These results point to an enhanced reliance of CA1 on the direct “sensory” cortical input and a suppressed processing of learned and stored information from the CA3.…”

“…Trisynaptic loop models of impaired pattern separation in schizophrenia. A, DG hypofunction model: A dysfunctional dentate gyrus impairs pattern separation, CA3 is hyperactive (adapted from Tamminga et al) B, CA3‐CA1 disconnection model: Functional disconnection of CA3 and CA1 —as observed after systemic MK‐801 by Buchtova et al— may also manifest as impaired pattern separation. EC II, second layer of the entorhinal cortex; DG, dentate gyrus; SUB, subiculum…”

“…A disorganization of HPC ensemble activity patterns paired with a loss of ensemble code for (spatial) context and impaired cognitive (spatial) coordination on a rotating arena (Carousel) have been observed in CA1 of rats after the systemic NMDAR antagonists PCP and MK‐801 . Aberrant ensemble code for spatial context after systemic MK‐801 was found in rat CA1, but not in CA3 . This uncoupling may reflect an altered balance between CA1 inputs in favour of the temporoammonic pathway and resulting reduced precision of memory of prior experience from CA3 relative to sensory input from EC.…”

Morphological Changes of the Rat Hippocampal Neurons Following Excessive Fluoride Consumption

“…Интрагиппокампальная обработка информации CA3 также важна для формирования моделей поведения на основе имеющегося опыта и может модулировать активность зоны CA1 [20]. Кроме того, нарушение связи между зонами (даже без повреждений нейронов) негативно влияет на способность формирования долговременной памяти [6].…”

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