Elimination of the vesicular acetylcholine transporter in the forebrain causes hyperactivity and deficits in spatial memory and long-term potentiation

Abstract

Basal forebrain cholinergic neurons, which innervate the hippocampus and cortex, have been implicated in many forms of cognitive function. Immunolesion-based methods in animal models have been widely used to study the role of acetylcholine (ACh) neurotransmission in these processes, with variable results. Cholinergic neurons have been shown to release both glutamate and ACh, making it difficult to deduce the specific contribution of each neurotransmitter on cognition when neurons are eliminated. Understanding the precise roles of ACh in learning and memory is critical because drugs that preserve ACh are used as treatment for cognitive deficits. It is therefore important to define which cholinergic-dependent behaviors could be improved pharmacologically. Here we investigate the contributions of forebrain ACh on hippocampal synaptic plasticity and cognitive behavior by selective elimination of the vesicular ACh transporter, which interferes with synaptic storage and release of ACh. We show that elimination of vesicular ACh transporter in the hippocampus results in deficits in long-term potentiation and causes selective deficits in spatial memory. Moreover, decreased cholinergic tone in the forebrain is linked to hyperactivity, without changes in anxiety or depression-related behavior. These data uncover the specific contribution of forebrain cholinergic tone for synaptic plasticity and behavior. Moreover, these experiments define specific cognitive functions that could be targeted by cholinergic replacement therapy.Alzheimer's disease | Morris water maze | synaptic vesicle | Barnes maze T he mechanisms that underlie the formation of hippocampaldependent spatial memory have been broadly explored (1). However, the neurochemical basis underlying changes in the strength of synaptic connections necessary for memories to persist is still not precisely understood. In the case of the hippocampus, mechanisms for memory processing include mRNA-dependent (2) and mammalian target of rapamycin (mTOR)-mediated protein synthesis (3) as well as a sequence of biochemical events shared with or closely similar to that of long-term potentiation (LTP) (2). Indeed, the consolidation of two different aversive tasks (4) and of spatial recognition memory (5) is accompanied by LTP of the CA3-CA1 synapse and can be occluded by a preceding LTP.The basal forebrain cholinergic system, which innervates the hippocampus and cortex, has been suggested to modulate LTP in the hippocampus (6-9) and has been implicated in many forms of behavior (10). In addition, spatial memory has also been suggested to depend on cholinergic activity (10), although there are numerous controversies surrounding which behaviors acetylcholine (ACh) regulates (11, 12). Moreover, in few studies cholinergic denervation did not affect expression of LTP (13). Understanding the precise roles of ACh in learning and memory is of importance because in different types of dementia cholinergic function is decreased (14), and manipulations that boost ACh levels at synapses are used a...

Fear Memory

“…It is premature to conclude if any application based on that research would be forthcoming, as indeed it is premature to make any optimistic predictions in the case of any of the many purported drug treatments for memory disorders. This will become even more apparent when we deal in section IX with the diverse memory modulatory systems known to act on the biochemical basis of memory (393), whose actions are linked to the data commented above in this subsection.…”

“…Research on the role of ACh in cognition recently became more centered into specific aspects of cognition, including the cognition of fear, and thus more interesting and likely to give results one can work better with (393). One of the latest major acquisitions in the field has been the use of transgenic mice with a decreased expression of the rapid vesicular transporter of choline back to the synapses that released it (VAChT) (317,393,506).…”

“…The cellular consolidation of IA triggers and is accompanied by hippocampal NMDA-dependent LTP. The findings in hippocampal CA1 region during or after IA and during LTP have been obtained usually with a combination of different procedures and techniques (biochemical measurements, microinfusions into CA1 in behaving animals of inhibitors, and stimulants of various enzymes or receptors at specific times) (265,272,273,291,649) and with the use of transgenic animals hyper-or hypo-expressing a particular enzyme or receptor (354,393,397,518), so they seem to be on the whole very well founded.…”

“…One of the latest major acquisitions in the field has been the use of transgenic mice with a decreased expression of the rapid vesicular transporter of choline back to the synapses that released it (VAChT) (317,393,506). Animals with different degrees of cholinergic damage can be produced (506).…”

New frontiers in the study of memory mechanisms

“…13,15 A role for PKMzeta in memory Clearly, then, hippocampal LTP is at the center of the initial, post-acquisition process of memory consolidation. [11][12][13][14][15][16][17][18][19] It has recently been shown to be one of the very few attributes of memory that is partly modulated by cholinergic transmission, 20 which explains the effect of pro-cholinergic drugs on memory impairments.…”