Medial septal β-amyloid 1-40 injections alter septo-hippocampal anatomy and function

Abstract

Degeneration of septal neurons in Alzheimer's disease (AD) results in abnormal information processing at cortical circuits and consequent brain dysfunction. The septum modulates the activity of hippocampal and cortical circuits and is crucial to the initiation and occurrence of oscillatory activities such as the hippocampal theta rhythm. Previous studies suggest that amyloid β peptide (Aβ) accumulation may trigger degeneration in AD. This study evaluates the effects of single injections of Aβ 1-40 into the medial septum. Immunohistochemistry revealed a decrease in septal cholinergic (57%) and glutamatergic (53%) neurons in Aβ 1-40 treated tissue. Additionally, glutamatergic terminals were significantly less in Aβ treated tissue. In contrast, septal GABAergic neurons were spared. Unitary recordings from septal neurons and hippocampal field potentials revealed an approximately 50% increase in firing rates of slow firing septal neurons during theta rhythm and large irregular amplitude (LIA) hippocampal activities and a significantly reduced hippocampal theta rhythm power (49%) in Aβ 1-40 treated tissue. Aβ also markedly reduced the proportion of slow firing septal neurons correlated to the hippocampal theta rhythm by 96%. These results confirm that Aβ alters the anatomy and physiology of the medial septum contributing to septohippocampal dysfunction. The Aβ induced injury of septal cholinergic and glutamatergic networks may contribute to an altered hippocampal theta rhythm which may underlie the memory loss typically observed in AD patients.

Decreased Rhythmic GABAergic Septal Activity and Memory-Associated θ Oscillations after Hippocampal Amyloid-β Pathology in the Rat

“…An examination of the local microenvironment around A␤ deposits in the hippocampus confirms that focal A␤40 and A␤42 injections in rats trigger long-lasting microglial activation (Weldon et al, 1998;Stéphan et al, 2003;Colom et al, 2010), as observed in the brain of AD patients (for review, see Akiyama et al, 2000). This microglial activation contributes to neuronal alterations, including a local loss of dendritic spines and axonal dystrophy, as well as modifications in the functional properties of neurons (Busche et al, 2008;Meyer-Luehmann et al, 2008).…”

Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease

“…Additionally, we analyzed immunoreactivity to NeuN, which is a general neuronal marker, (Colom et al, 2010) and Syn2 in the cortex, hippocampus and CPu. Syn2 is a presynaptic vesicle protein located in axons (Tarsa and Goda, 2002) and its increased level is correlated to improvement of cognitive function in rodents (Mulder et al, 2004).…”

Beta-amyloid induced changes in A-type K+ current can alter hippocampo-septal network dynamics

“…Although in this work, we only focus on the system dynamical changes caused by the pathological changes in the hippocampal pyramidal neurons, it should be admitted that the Aβ-indued hippocampal dysfunction may be more complex. For example, it has been shown in (Villette et al 2010;Colom et al 2010) that Aβ-induced GABAergic and cholinergic system degeneration in the medial septum may also cause hippocampal dysfunctions. GABAergic neurons inhibit hippocampal OLM and basket neurons and act as a hippocampal theta rhythm pacemaker and cholinergic neurons control the acetylcholine level in the hippocampus, which can change the dynamics of pyramidal neurons and synapses.…”