Integrity of mGluR-LTD in the Associative/Commissural Inputs to CA3 Correlates with Successful Aging in Rats

Abstract

The impact of aging on cognitive capabilities varies among individuals ranging from significant impairment to preservation of function on par with younger adults. Research on the neural basis for age-related memory decline has focused primarily on the CA1 region of the hippocampus. However, recent studies in elderly human and rodents indicate that individual differences in cognitive aging are more strongly tied to functional alterations in CA3 circuits. To examine synaptic plasticity in the CA3 region, we used aged rats behaviorally characterized in a hippocampal-dependent task to evaluate the status of long-term potentiation and long-term depression (LTP and LTD) in the associative/commissural pathway (A/C3 CA3), which provides the majority of excitatory input to CA3 pyramidal neurons. We found that, unlike in CA1 synapses, in A/C3 CA3 LTP is minimally affected by age. However, two forms of LTD, involving NMDA and metabotropic glutamate receptors (mGluR), are both greatly reduced in age-impaired rats. Age-unimpaired rats, in contrast, had intact mGluR LTD. These findings indicate that the integrity of mGluR-LTD at A/C3 CA3 inputs may play a crucial role in maintaining the performance of CA3 circuitry in aging.

Glutamate presynaptic vesicular transporter and postsynaptic receptor levels correlate with spatial memory status in aging rat models

“…For example, recognition memory is impaired in 24-month-old SD rats, and this deficit is associated with reduced NMDA-mediated plasticity (Kollen et al, 2010). Group I mGluR signaling and function have also recently been correlated with intact spatial memory in aged rats (Menard and Quirion, 2012b;Yang et al, 2013) and mice .…”

Interlamellar CA1 network in the hippocampus

“…Such connections are able to learn to associate components of an input pattern with each other (2), which, in turn, has greatly influenced thinking on the mechanisms of memory formation and recall (3). Under appropriate conditions, computer simulations reveal that recurrent neural networks have the capacity to learn temporal sequences and to carry out pattern completion (4,5). Interestingly, although they are quite near to the CA3 region, CA1 pyramidal neurons reportedly form remarkably few associational connections (6,7).…”

Signaling Pathways Relevant to Cognition-Enhancing Drug Targets

“…Our group and others have recently highlighted the importance of group 1 mGluRrelated synaptic plasticity in successful cognitive aging (Menard and Quirion 2012b;Menard et al 2013bMenard et al , 2014bYang et al 2013a). Eight mGluR have been identified and divided into three groups: group 1 includes postsynaptic mGluR1 and mGluR5, while group 2 (mGluR2, mGluR3) and group 3 (mGluR4, mGluR6, mGluR7, mGluR8) are mainly presynaptic (for a review, see Nicoletti et al 2011).…”

“…This type of memory involves efficient pattern separation and inhibitory learning processes which can be affected by aging Menard and Quirion 2012b;Menard et al 2013b). Stimulation of group 1 mGluRs could act as a molecular switch to facilitate synaptic plasticity (Bortolotto et al 2005;Manahan-Vaughan and Braunewell 2005;Bikbaev et al 2008;Neyman and Manahan-Vaughan 2008) particularly in the aging brain (Menard and Quirion 2012a, b;Menard et al 2013bMenard et al , 2014bYang et al 2013a). …”