Pflugers Arch. 2014 Jul;466(7):1437-50. doi: 10.1007/s00424-013-1368-z. Epub 2013 Oct 17.

Firing properties of entorhinal cortex neurons and early alterations in an Alzheimer’s disease transgenic model.

Andrea Marcantoni1,2,*, Elisabeth F. Raymond1, Emilio Carbone2, Hélène Marie1,*

1 Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, 06560 Valbonne, France.

2 Department of Drug Science, Lab of Cellular & Molecular Neuroscience, University of Turin, Italy


The entorhinal cortex (EC) is divided into medial (MEC) and lateral (LEC) anatomical areas, and layer II neurons of these two regions project to granule cells of the dentate gyrus through the medial and lateral perforant pathways (MPP and LPP), respectively. Stellate cells (SCs) represent the main neurons constituting the MPP inputs, while fan cells (FCs) represent the main LPP inputs. Here, we first characterized the excitability properties of SCs and FCs in adult wild-type (WT) mouse brain. Our data indicate that, during sustained depolarization, action potentials (APs) generated by SCs exhibit increased fast afterhyperpolarization and overshoot, making them able to fire at higher frequencies and to exhibit higher spike frequency adaptation (SFA) than FCs. Since the EC is one of the earliest brain regions affected during Alzheimer’s disease (AD) progression, we compared SCs and FCs firing in 4-month-old WT and transgenic Tg2576 mice, a well-established AD mouse model. Tg2576-SCs displayed a slight increase in firing frequency during mild depolarization but otherwise normal excitability properties during higher stimulations. On the contrary, Tg2576-FCs exhibited a decreased firing frequency during mild and higher depolarizations, as well as an increased SFA. Our data identify the FCs as a neuronal population particularly sensitive to early pathological effects of chronic accumulation of APP-derived peptides, as it occurs in Tg2576 mice. As FCs represent the major input of sensory information to the hippocampus during memory acquisition, early alterations in their excitability profile could significantly contribute to the onset of cognitive decline in AD.

PMID: 24132829



Identifying the cellular and molecular mechanisms that underlie Alzheimer’s disease (AD) cognitive decline is a key issue of current research and most studies have so far investigated the degree of AD progression by electrophysiological analysis focused on hippocampal plasticity and excitability [1, 2] . To date, very little information is available on the functional properties of entorhinal cortex (EC) neurons in this pathology. Yet, the EC is one of the first human brain structures to be affected in AD and represents the main input and output to and from the hippocampus (Fig.1)


fig1Fig.1 The main source of afferent input to the hippocampus is represented by the entorhinal cortex (EC) that forms a major part of what is termed parahippocampal area. Neurons in superficial layers of the EC form synapses via the lateral and medial perforant pathway (LPP, MPP) in all hippocampal subregions, with the largest projection connecting to the granule cells (GCs) of dentate gyrus (DG). From the DG granule cells, axons forming the mossy fiber pathway connect to the pyramidal cells in area CA3, which in turn project to the pyramidal cells in CA1 by means of the Schaffer collaterals.  Pathway. The principal output of the CA1 is directed towards the EC [1].


Correct EC function is crucial to convey the necessary information for sensory and spatial processing to the hippocampus, which further processes this information to form episodic memories. As this type of memory is strongly affected in AD at the onset of cognitive decline, investigating the functional integrity of EC in this disease is of major importance.

The study was performed using the well known mouse model of AD, the Tg2576 mouse, which displays several key features of AD pathology [3]: 1) accumulation of the amyloid-β peptide in the medial temporal lobes, including the EC, and 2) an age-dependent decline in hippocampus-dependent memory. After having previously identified the onset of this cognitive decline from 3 months of age in this mouse model [4], here we investigated in these early symptomatic Tg2576 mice the functional integrity of the EC neurons (the stellate, SCs, and fan cells, FCs), which constitute the main input neurons to the hippocampus. Using whole-cell electrophysiology, we first described the properties of these neurons in age-matched wild type (WT) mice. We then demonstrated that, while the excitability properties of SC neurons are only slightly altered in the Tg2576 mice, the FC neurons display significant alterations in their intrinsic excitability profile, summarized  s an average firing frequency decrease (Fig.2) as well as an increased spike frequency adaptation (not shown). These findings are in good agreement with other recent reports showing that, during the early phase, neurons from LEC are already functionally altered [5, 6]. This also underlines the importance of LEC alterations at early stages when the AD typically displays a prolonged and asymptomatic window that precedes the onset of memory loss symptoms [7].

The significance of this study is thus two-fold. First: it prompts further studies toward the identification of altered mechanisms of somatosensory stimuli and related memory processing through the LEC in elderly patients without AD symptoms. These studies will help clarifying if impairments of LEC-mediated memory can be considered predictive of AD onset. Second: it suggests that LEC neurons could be a pharmacological target for AD treatment during the early phase of the pathology. Thus allowing the development of drugs and/or therapies, which may either interrupt or slow down AD progression.


Fig.2 a) Representative transmitted light microscopy image of a freshly prepared hippocampal-entorhinal cortex slice. Inserts represent magnified images of two SCs about to be patched, displaying characteristic stellate shape morphology typical of both SCs and FCs. b) Action potential (AP) responses during injection of 550 pA current steps in WT (top) were comparable to that measured in Tg2576 SCs (bottom), as shown in panel c where the mean firing frequencies were plotted versus injected current in WT and Tg2576 SCs. d) when AP firing frequencies were measured in FCs from WT (d, top) and compared to Tg2576 (d, bottom) we noticed a significant decreased value in these latter as described in panel e.



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